Mammalian MSC from Selected Species: Features and Applications
Christiane Uder, Sandra Br€uckner, Sandra Winkler, Hans-Michael Tautenhahn,†‡ Bruno Christ†*
Mesenchymal stromal/stem cells (MSC) are promising candidates for cellular therapy of different diseases in humans and in animals. Following the guidelines of the International Society for Cell Therapy, human MSC may be identified by expression of a specific panel of cell surface markers (CD1051, CD731, CD901, CD34-, CD14-, or CD11b-, CD79- or CD19-, HLA-DR-). In addition, multiple differentiation potential into at least the osteogenic, adipogenic, and chondrogenic lineage is a main criterion for MSC definition. Human MSC and MSC of a variety of mammals isolated from different tissues meet these criteria. In addition to the abovementioned, they express many more cell surface markers. Yet, these are not uniquely expressed by MSC. The gross phenotypic appearance like marker expression and differentiation potential is similar albeit not identical for MSC from different tissues and species. Similarly, MSC may feature different biological characteristics depending on the tissue source and the isolation and culture procedures. Their versatile biological qualities comprising immunomodulatory, anti-inflammatory, and proregenerative capacities rely largely on the migratory and secretory capabilities of MSC. They are attracted to sites of tissue lesion and secrete factors to promote self-repair of the injured tissue. This is a big perspective for clinical MSC applications in both veterinary and human medicine. Phase I/II clinical trials have been initiated to assess safety and feasibility of MSC therapies in acute and chronic disease settings. Yet, since the mode of MSC action in a specific disease environment is still unknown at large, it is mandatory to unravel the response of MSC from a given source onto a specific disease environment in suitable animal models prior to clinical applications.
International Journal of Stem Cell Research and Transplantation (IJST) is a peer-reviewed journal, and is dedicated to providing information with respect to the latest advancements that are being upgraded in our everyday life with respect to the application of Stem cells.
International Journal of Stem Cell Research and Transplantation (IJST) ISSN:2328-3548, is a free, Open Access, Peer-reviewed, exclusive online journal covering areas of Stem cell research, translational work and Clinical studies in the specialty of Stem Cells and Transplantation including allied specialties relevant to the core subject, which is dedicated in publishing high quality manuscripts.
International Journal of Stem Cell Research and Transplantation (IJST) is an international, Open Access, peer-reviewed journal, which mainly focuses, on the advancements made in the field of cell biology, specifically in the field of Stem Cells.
Stem cells have the ability to perpetuate themselves through self-renewal and generate mature cells of a particular tissue through differentiation. Mesenchymal Stem Cells (MSCs) play an important role in tissue homeostasis supporting tissue regeneration. MSCs are rare pluripotent cells supporting hematopoietic and mesenchymal cell lineages. MSCs have a great potential in cancer therapy, also the stem cell exosome and/or microvesicle-mediated tissue regeneration abilities may be used a potential to the therapeutic applications. In this review, use of hMSCs in stem cell-mediated cancer therapy is discussed.
describe two recent scientific research studies and it therapies inv.pdffeelingcomputors
describe two recent scientific research studies and it therapies involving stem cells. Explain what
the researches did(how the study was performed).the result and conclusion
Solution
Therapies for wound healing:
Wound healing is a dynamic process bleeding and coagulation, acute inflammation, cell
migration, proliferation, differentiation, angiogenesis, re-epithelialization, and synthesis and
remodeling of the extracellular matrix. Many local and systemic factors can impair wound
healing process resulting in prolonged and non-healing chronic wounds which affects the quality
of patients’life. Stem cell-based therapy represents a promising therapeutic approach for wound
healing. Stem cells have been shown to mobilize and find home for ischemic and wounded
tissues where they secrete chemokines and growth factors to promote angiogenesis and
extracellular matrix remodeling.
In wounds, It has been reported that Mesenchymal stem cells are recruited to wound skin at the
time of wound healing and have the capacity to differentiate into multiple skin cell types
including keratinocytes, endothelial cells and pericytes. Furthermore, circulating MSC
recruitment was induced by a specific chemokine (SLC/CCL21)/chemokine receptor (CCR7)
interaction both in vitro and in vivo. Intradermal injection of SLC/CCL21 significantly
accelerated wound closure by increasing rates of MSC accumulation, especially the formation of
endothelial transdifferentiated cells (Sasaki et al., 2008) . MSCs are good candidate which can be
transdifferentiated into endothelial cells and epithelial- fibroblast cells for wound repair therapy
and understanding there signaling mechanism can further help in regenerative medicine.
Mesenchymal stem cells (MSC), referred as mesenchymal stromal cells , colony forming unit-
fibroblasts and mesenchymal progenitor cells , were first identified by Friedenstein as
subpopulation of bone marrow cells. Other than hemopoietic stem cells and differentiated
lineages, bone marrow contains a subset of nonhemopoietic cells, mesenchymal stem cells
(MSCs) that account for roughly 0.01–0.001% of the bone marrow derived cell population .
These are a rare population of non-hematopoietic stromal cells, present in the bone marrow and
most connective tissues of the body.They have capability to proliferate in vitro in uncommitted
state and retain their multilineage differentiation potency which make them attractive candidates
for biological cell-based tissue repair approaches. These cells have ability to differentiate into
three mesenchymal lineages: adipogenic , osteogenic, chondrogenic and can be induced to
commit to various other phenotypes like neurogenic, hepatocytes,myogenic, tenocytes,
cardiomyocytes, fibroblast and endothelial cells. In vivo studies have also shown that MSCs can
differentiate into tissue-specific cells in response to cues provided by different organs . In
addition to pluripotency, MSCs are known to have immunosuppressive effects involving vari.
Mammalian MSC from Selected Species: Features and Applications
Christiane Uder, Sandra Br€uckner, Sandra Winkler, Hans-Michael Tautenhahn,†‡ Bruno Christ†*
Mesenchymal stromal/stem cells (MSC) are promising candidates for cellular therapy of different diseases in humans and in animals. Following the guidelines of the International Society for Cell Therapy, human MSC may be identified by expression of a specific panel of cell surface markers (CD1051, CD731, CD901, CD34-, CD14-, or CD11b-, CD79- or CD19-, HLA-DR-). In addition, multiple differentiation potential into at least the osteogenic, adipogenic, and chondrogenic lineage is a main criterion for MSC definition. Human MSC and MSC of a variety of mammals isolated from different tissues meet these criteria. In addition to the abovementioned, they express many more cell surface markers. Yet, these are not uniquely expressed by MSC. The gross phenotypic appearance like marker expression and differentiation potential is similar albeit not identical for MSC from different tissues and species. Similarly, MSC may feature different biological characteristics depending on the tissue source and the isolation and culture procedures. Their versatile biological qualities comprising immunomodulatory, anti-inflammatory, and proregenerative capacities rely largely on the migratory and secretory capabilities of MSC. They are attracted to sites of tissue lesion and secrete factors to promote self-repair of the injured tissue. This is a big perspective for clinical MSC applications in both veterinary and human medicine. Phase I/II clinical trials have been initiated to assess safety and feasibility of MSC therapies in acute and chronic disease settings. Yet, since the mode of MSC action in a specific disease environment is still unknown at large, it is mandatory to unravel the response of MSC from a given source onto a specific disease environment in suitable animal models prior to clinical applications.
International Journal of Stem Cell Research and Transplantation (IJST) is a peer-reviewed journal, and is dedicated to providing information with respect to the latest advancements that are being upgraded in our everyday life with respect to the application of Stem cells.
International Journal of Stem Cell Research and Transplantation (IJST) ISSN:2328-3548, is a free, Open Access, Peer-reviewed, exclusive online journal covering areas of Stem cell research, translational work and Clinical studies in the specialty of Stem Cells and Transplantation including allied specialties relevant to the core subject, which is dedicated in publishing high quality manuscripts.
International Journal of Stem Cell Research and Transplantation (IJST) is an international, Open Access, peer-reviewed journal, which mainly focuses, on the advancements made in the field of cell biology, specifically in the field of Stem Cells.
Stem cells have the ability to perpetuate themselves through self-renewal and generate mature cells of a particular tissue through differentiation. Mesenchymal Stem Cells (MSCs) play an important role in tissue homeostasis supporting tissue regeneration. MSCs are rare pluripotent cells supporting hematopoietic and mesenchymal cell lineages. MSCs have a great potential in cancer therapy, also the stem cell exosome and/or microvesicle-mediated tissue regeneration abilities may be used a potential to the therapeutic applications. In this review, use of hMSCs in stem cell-mediated cancer therapy is discussed.
describe two recent scientific research studies and it therapies inv.pdffeelingcomputors
describe two recent scientific research studies and it therapies involving stem cells. Explain what
the researches did(how the study was performed).the result and conclusion
Solution
Therapies for wound healing:
Wound healing is a dynamic process bleeding and coagulation, acute inflammation, cell
migration, proliferation, differentiation, angiogenesis, re-epithelialization, and synthesis and
remodeling of the extracellular matrix. Many local and systemic factors can impair wound
healing process resulting in prolonged and non-healing chronic wounds which affects the quality
of patients’life. Stem cell-based therapy represents a promising therapeutic approach for wound
healing. Stem cells have been shown to mobilize and find home for ischemic and wounded
tissues where they secrete chemokines and growth factors to promote angiogenesis and
extracellular matrix remodeling.
In wounds, It has been reported that Mesenchymal stem cells are recruited to wound skin at the
time of wound healing and have the capacity to differentiate into multiple skin cell types
including keratinocytes, endothelial cells and pericytes. Furthermore, circulating MSC
recruitment was induced by a specific chemokine (SLC/CCL21)/chemokine receptor (CCR7)
interaction both in vitro and in vivo. Intradermal injection of SLC/CCL21 significantly
accelerated wound closure by increasing rates of MSC accumulation, especially the formation of
endothelial transdifferentiated cells (Sasaki et al., 2008) . MSCs are good candidate which can be
transdifferentiated into endothelial cells and epithelial- fibroblast cells for wound repair therapy
and understanding there signaling mechanism can further help in regenerative medicine.
Mesenchymal stem cells (MSC), referred as mesenchymal stromal cells , colony forming unit-
fibroblasts and mesenchymal progenitor cells , were first identified by Friedenstein as
subpopulation of bone marrow cells. Other than hemopoietic stem cells and differentiated
lineages, bone marrow contains a subset of nonhemopoietic cells, mesenchymal stem cells
(MSCs) that account for roughly 0.01–0.001% of the bone marrow derived cell population .
These are a rare population of non-hematopoietic stromal cells, present in the bone marrow and
most connective tissues of the body.They have capability to proliferate in vitro in uncommitted
state and retain their multilineage differentiation potency which make them attractive candidates
for biological cell-based tissue repair approaches. These cells have ability to differentiate into
three mesenchymal lineages: adipogenic , osteogenic, chondrogenic and can be induced to
commit to various other phenotypes like neurogenic, hepatocytes,myogenic, tenocytes,
cardiomyocytes, fibroblast and endothelial cells. In vivo studies have also shown that MSCs can
differentiate into tissue-specific cells in response to cues provided by different organs . In
addition to pluripotency, MSCs are known to have immunosuppressive effects involving vari.
REVIEWCancer stem cells a new framework for the designo.docxjoellemurphey
REVIEW
Cancer stem cells: a new framework for the design
of tumor therapies
Boyan K. Garvalov & Till Acker
Received: 14 July 2010 /Revised: 27 August 2010 /Accepted: 16 September 2010
# Springer-Verlag 2010
Abstract Modern tumor therapy has achieved considerable
progress, but many tumors remain refractory to treatment or
relapse following initial remission. Recent evidence points
to one possible reason for this limited therapeutic efficiency:
that the design of anticancer agents so far may not have been
aimed at the right target. While conventional tumor therapies
have targeted the main mass of tumor cells, there is now
compelling evidence that tumor initiation and progression are
driven by a subpopulation of tumor cells that possess stem cell
properties and are resistant to traditional cancer treatments—
the cancer stem cells (CSCs). CSCs have been identified in
most types of cancer and can be separated from the rest of the
tumor cells using appropriate markers. CSCs are regulated by
molecular mechanisms and specific, perivascular, and hypox-
ic microenvironments, which largely overlap with those
controlling stem cells from normal tissues. Our improved
understanding of CSC biology has already provided a number
of novel targets and drug discovery platforms for the design of
specific therapies that aim to eradicate the CSC subpopula-
tion. Therapeutic approaches can be targeted either at
eliminating the CSCs themselves or at disrupting the niches
in which CSCs reside. Moreover, the importance of CSCs for
tumor growth, resistance, and progression implies that clinical
trials and preclinical studies of anticancer therapies should
include as a key element an assessment of the abundance and
persistence of CSCs. Thus, CSC research holds great promise
for providing important new impetus to the fields of tumor
biology and clinical oncology.
Keywords Cancer stem cell . Hypoxia .
Microenvironment . Angiogenesis . Antitumor therapy.
Metastasis
The hierarchy model and cancer stem cells (CSCs)
The classical view of tumor formation is based on the
“stochastic” or “clonal evolution” model [1, 2]. It perceives
the tumor as a mass of hyperproliferative cells with similar
potential for driving tumor growth. Tumor heterogeneity
and progression are seen as the result of variations in the
tumor microenvironment and genetic mutations in individ-
ual cells, followed by selection of those that are best
adapted to support the further growth of the tumor (Fig. 1a).
An alternative concept that has been gaining increasing
experimental support is the “hierarchy” or “cancer stem
cell” model [3]. This model posits that tumors are generated
and maintained in a manner similar to the physiological
stem cell system operating in normal tissues, i.e., by cells
with stem cell-like properties, which self-renew and
differentiate into the distinct cellular subtypes of the tumor
(Fig. 1b). The key novel features of this model are that only
a limited population of tumor cell ...
Cancer Stem Cells and the Unicellular Life Cycle of Cancer_Crimson PublishersCrimsonpublishersCancer
All eukaryotes, from protists to mammalians, preserve a unicellular life cycle inherited from the common ancestor that can be reactivated under unfavorable living conditions. The cell-of-origin of cancer escapes its death by forming a protected polyploid cyst-like structure (CLS), that starts the unicellular life cycle of cancer. The reversal to unicellularity occurs through genomic and epigenetic alterations that activate the MUT switch of early Metazoans and not through mutations. The microcell progeny of CLSs spread into tissues and organs and form the CSC pool of aCLS cancers. Depending on the environment, the CSC pool differentiates a reproductive cell subline, which forms new aCLSs by cyclic encystment and asymmetric cell division, or a somatic subline, which proliferates strongly by symmetric cell division without cyst differentiation.
Stem cells have unique characteristics, they are unspecialized cells; they can reproduce itself over and over again through asymmetric cell division. There are different kinds of stem cells which depend on their originality and/ or their potency. Cell therapy is an emerging form of treatment for several diseases. Stem cells have generated incredible interest for repairing failing tissues and organs, which appeared to be the only reasonable therapeutic strategy. They seem to represent a future powerful tool in regenerative medicine, therefore, this review article aimed to elucidate the different sources of stem cells and their clinical applications
Adipose Tissue and Mesenchymal Stem Cells: State of the Art and Lipogems® Technology Development
Carlo Tremolada1 & Valeria Colombo1 & Carlo Ventura2
Abstract Inthepastfewyears,interestinadiposetissueasan ideal source of mesenchymal stem cells (MSCs) has increased. These cells are multipotent and may differentiate in vitro into several cellular lineages, such as adipocytes, chondrocytes, osteoblasts, and myoblasts. In addition, they secrete many bioactive molecules and thus are considered Bmini-drugstores.^ MSCs are being used increasingly for many clinical applications, such as orthopedic, plastic, and reconstructive surgery. Adipose-derived MSCs are routinely obtained enzymatically from fat lipoaspirate as SVF and/or may undergo prolonged ex vivo expansion, with significant senescence and a decrease in multipotency, leading to unsatisfactory clinicalresults.Moreover, these techniquesare hampered by complex regulatory issues. Therefore, an innovative technique (Lipogems®; Lipogems International SpA, Milan, Italy) was developed to obtain microfragmented adipose tissue with an intact stromal vascular niche and MSCs with a high regenerative capacity. The Lipogems® technology, patented in 2010 and clinically available since 2013, is an easyto-use system designed to harvest, process, and inject refined fat tissue and is characterized by optimal handling ability and a great regenerative potential based on adipose-derived MSCs. In this novel technology, the adipose tissue is washed, emulsified, and rinsed and adipose cluster dimensions gradually are reduced to about 0.3 to 0.8 mm. In the resulting
Lipogems® product, pericytes are retained within an intact stromal vascular niche and are ready to interact with the recipient tissue after transplantation, thereby becoming MSCs and starting the regenerative process. Lipogems® has been used in more than 7000 patients worldwide in aesthetic medicineandsurgery,aswellasinorthopedicandgeneralsurgery, with remarkable and promising results and seemingly no drawbacks. Now, several clinical trials are under way to supporttheinitialencouragingoutcomes.Lipogems®technology is emerging as a valid intraoperative system to obtain an optimal final product that may be used immediately for regenerative purposes.
Sox2gene experssion on mouse embryonic stem cells in the neural diffrentiationKhalid Mukhtar
Stem cells (SCs) are important cells for replacement therapy diseases.The interest in the potential of neural stem cells (NSCs) for the treatment of neurodegenerative diseases and brain injuries has substantially promoted research on neural stem cell self-renewal and differentiation.The geneissrybox containing gene 2 (Sox2) has been associated with a SC phenotype that predicts for poor outcomes. Sox2 is a transcription factor that regulates embryonic stem cell pluripotency and drives commitment of airway precursor cells to basal-type and neuroendocrine cells in the developing lung. Sox2gene involved will be investigated in practical pirogue according to the expression patterns.Sox2 has been associated with a SC phenotype that predicts for poor outcomes. Subsequently, information has been compiled on the question how Sox2 in neural differentiation is controlled on the molecular level, and controlled in vivo.
The definition of tissue engineering, according to International Union of Pure and Applied Chemistry (IUPAC), is “to use of a combination of cells, engineering and materials, and suitable biochemical and physiochemical factors to improve or replace biological functions
Cell Therapy: The New Approach to Dermatology and Dermatologic Surgerysemualkaira
Cell therapy is a viable alternative for the treatment of disease and tissue degeneration that is very effective, reliable and incurs minimal adverse effects on the body. Its successful application extends to all fields of medicine, including dermatology.
Stem cell therapy for the bladder has been conducted mainly on an experimental basis in the areas of bladder dysfunction. The therapeutic efficacy of stem cells was originally thought to be derived from their ability to differentiate into various cell types. For more details visit: http://www.cryobanksindia.com/moms-corner/case-studies/
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
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micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
2. Mesenchymal Stem Cells Derived from Wharton's Jelly Current Stem Cell Research & Therapy, 2013, Vol. 8, No. 2 145
cells [14]) in BM-aspirates and in addition their qualitative
and quantitative properties decline with donor's age [15].
The low frequency implies that an extensive in vitro expan-
sion of cells is usually required to obtain sufficient cell num-
bers for therapeutic interventions, thereby enhancing the risk
of epigenetic damages as well as viral and bacterial contami-
nations. To circumvent these obstacles, much effort has been
invested over the last decade in identifying alternative, more
abundant and easily attainable sources of MSCs for thera-
peutic use. In this regard the umbilical cord (UC), which is
considered medical waste and is obtained with a painless,
simple and safe procedure during delivery, has aroused much
attention during the last years as a promising source for MSC
isolation. MSCs have actually been found in both UC blood
(UCB) as well as in UC tissues. Nevertheless, the scarcity of
MSC in UCB (their frequency being much lower than in
BM) and the lack of a robust and reproducible technique for
harvesting and expanding MSCs from UCB units [16, 17]
have hampered their use in clinical applications. On the other
hand existing isolation protocols have constantly induced the
harvest of large numbers of MSCs from UC-tissues with a
hundred per cent success.
UC-MSCs share many properties with adult BM-MSCs,
but are generally considered as a more primitive population
than the latter. In fact, while they possess several characteris-
tics of ESCs, they do not form teratomas upon transplanta-
tion [18] and their research does not raise ethical or legal
issues. All these features open attractive perspectives for the
propagation and engineering of UC-derived MSCs for cell-
based therapies. This review will first attempt to give a
summary of the biology of MSCs derived from Wharton's
Jelly (WJ-MSCs), the most abundant region of UC and then
discuss their potential application for the treatment of cancer
and immune mediated disorders such as graft versus host
disease (GVHD) and systemic lupus erythematosus (SLE).
Finally, their putative role as feeder layers for ex vivo hema-
topoietic stem cell (HSC) expansion will be pointed out.
Human Umbilical Cord is a Rich Source of MSCs
The human UC (Fig. 1) contains two arteries and a vein
buried within a mucous or gelatinous connective tissue also
known as the Wharton’s jelly (WJ), enclosed by a simple
amniotic epithelium. WJ is largely made from proteoglycans
and various types of collagen, forming a sponge-like tissue,
within which stromal cells are embedded [19]. These cells,
also referred to as umbilical cord matrix (UCM) cells are
thought to be trapped into the WJ early in embryogenesis
during their migration from the aortic-gonadotropin-
mesonephric region to the fetal liver through the umbilical
cord [20]. UCM cells have exceptional properties in that
although they are bona fide MSCs [18, 21] as discussed be-
low in detail, possessing similar properties with their adult
BM counterparts, they also retain characteristics of primitive
stem cells, like the expression of embryonic stem cell mark-
ers [22, 23]. In line with these observations MSCs derived
from WJ, hereafter referred to as "UC-MSCs", maintain their
self-renewal capacity in vitro for a longer period of time, and
exhibit a shorter doubling time and a broader pluripotency as
compared to BM-MSCs [18]. These unique developmental
and operational characteristics along with the fact that UC-
MSCs can be easily isolated, extracorporeally without risks
for the donor, from a tissue which is routinely discarded,
highlight the advantages of UC-MSCs over ESCs and adult
MSCs and explain the rapidly growing interest in this field
of stem cell biology.
The first report providing robust evidence that WJ stro-
mal cells can be classified as MSCs was published in 2004
[24]. In that study, cells extracted from WJ, displayed a fi-
broblast-like phenotype when expanded in vitro and were
able to differentiate into osteoblasts, adipocytes and chon-
drocytes upon appropriate stimulation [24]. Furthermore,
akin to BM-MSCs they were shown to express high levels of
CD29, CD44, CD51, CD73 and CD105, but lacked expres-
sion of the hematopoietic markers CD34 and CD45 (Table 1)
[24]. Subsequent reports have provided additional informa-
Fig. (1). Umbilical cord contains two arteries and a vein, within a mucous or gelatinous connective tissue, the Wharton’s jelly, enclosed by a
simple amniotic epithelium. Mesenchymal stem cells have been isolated from umbilical cord blood and also from the intervascular, perivas-
cular and subamniotic regions of Wharton's jelly.
A
Wha
A
U bili l iUmbilical arteries
Perivascular
Intervasc
Amniotic epithelium
arton’s Jelly
Umbilical vein/
Umbilical cord blood
Amniotic epithelium
Subam
cular
nion
3. 146 Current Stem Cell Research & Therapy, 2013, Vol. 8, No. 2 Batsali et al.
tion on WJ stromal cell phenotype, demonstrating the ex-
pression of various membrane molecules known to be asso-
ciated with a MSC-like identity. These molecules include
CD90, CD146, CD166 and ganglioside 2 (GD2) [8, 23, 25,
26]. Collectively, the morphology, immunophenotype and
differentiation potential of WJ stromal cells fulfill the criteria
for MSCs proposed by the International Society for Cellular
Therapy (ISCT) [8]. Indeed, given that at present there is no
specific marker to define UC-MSCs, the expression of the
aforementioned set of membrane antigens combined with the
demonstration of in vitro multi-lineage differentiation poten-
tial is necessary to identify MSCs in UC-derived tissues
UC-MSCs have been isolated from three relatively indis-
tinct regions of the WJ: the perivascular, the intervascular
and the subamnion zones (Fig. 1) [27]. Cells from these
zones share a fibroblast-like morphology, a high proliferative
rate and multipotent differentiation capacity. However a
comprehensive head-to-head comparison between MSCs
obtained from different regions of the UC has not been per-
formed thus far, due to the great variation in cell isola-
tion/culture protocols. Hence the question whether cells har-
vested from different components of the UC represent differ-
ent populations is still open. Nevertheless one study combin-
ing both in situ and in vitro experiments [27] has demon-
strated that MSCs derived from the perivascular region com-
prise a distinct subpopulation than those derived from the
intervascular and subamniotic parts of the UC. It has thus
been reported that perivascular MSCs stain strongly for pan-
cytokeratin as compared to intervascular and subamniotic
counterparts and give rise in vitro to flat, wide cytoplasmic
cells, named type 1 cells, which tend to diminish in number
during protracted culture [27]. On the other hand intervascu-
lar and subamniotic MSCs generate fibroblast-like cells per-
sisting throughout culture (type 2 cells). In view of these
findings it appears that UC-MSCs are actually type 2 cells,
displaying adipogenic, chondrogenic, osteogenic and neu-
ronal capacity, upon appropriate differentiation stimuli [27].
Isolation of MSCs from UC perivascular zone has been re-
ported by other groups as well [28, 29]. These cells, termed
as Human Umbilical Cord Perivascular Cells (HUCPVCs),
have a colony forming unit (CFU) frequency of 1:333 [29]
and differ in their growth characteristics from UC-MSCs
(population doubling times ranging from 59.4±42.4h in pas-
sage 0 to nearly 20h in passage 6 for HUCPVCs versus
85±7.2h in passage 0 to 11±1.2h in passage 7 for a mixed
population of UC-MSCs [27, 29]. Furthermore, HUCPVCs
exhibit higher proliferative capacity and osteogenic potential
as compared to BM-MSCs [28]. The phenotype of
HUCPVCs shares many similarities with that of WJ-derived
MSCs (Table 1). One significant difference though, is the
high expression of CD146 by HUCPVCs. Interestingly this
marker is either absent [28] or weakly expressed by MSCs
derived form other regions of WJ [30].
Isolation of MSCs from Wharton's Jelly
In recent years, several methods (Fig. 2) have been de-
veloped for the isolation of MSCs from WJ. However, ex-
perimental approaches vary considerably and in some cases
harvested cells from UC tissue most likely consist of a het-
erogeneous population, thereby biasing comparisons. With
regards to protocols used to isolate UC-MSCs, some authors
remove umbilical cord vessels, scrape off WJ with a scalpel
and then treat the tissue enzymatically [24]. Others cut down
UC to smaller segments, strip the vessels and then directly
immerse the remaining UC to an enzymatic solution [25, 27,
31]. Interestingly, neither the enzymes used nor the incuba-
tion period have been standardized thus far. Alternatively,
instead of enzymatic digestion, several groups dissect the
cord segment into very small pieces, with or without discard-
ing the cord vessels and the segments are used as explants
from which cultures are subsequently established [32-34].
The major advantage of this method is that it minimizes cell
damage as it does not involve enzymatic treatment, however
it should be noted that primary cultures generated in this way
are quite heterogeneous [33]. UC-MSCs have also been iso-
lated from WJ by simply cutting UC segments longitudinally
and plating them with WJ side-down onto a plastic surface,
once again without enzyme digestion or dissection [35]. Fi-
nally, to collect HUCPVCs some groups remove blood ves-
sels together with surrounding WJ, tie up the ends of each
vessel into a loop and then immerse the vessel in enzyme,
thereby isolating cells from the perivascular tissue [28, 29].
The question as to which is the optimal method for effi-
cient isolation of a homogeneous and well defined popula-
tion of UC-MSCs has not been answered thus far. However,
unless an agreement is reached between laboratories regard-
ing the isolation and ex vivo expansion of UC-MSCs, there
will be no consensus on the characteristics and biological
properties of the cells, which is a prerequisite for the proper
design of preclinical studies, so as to pave the way for the
potential use of UC-MSCs in clinical applications.
Do differences in isolation procedures and ex vivo expan-
sion protocols have an impact on the antigens expressed by
UC-MSCs? This issue has not been properly investigated so
far, yet a recent study [36] demonstrated that MSC markers
CD73, CD90 and CD105 varied their expression patterns
according to whether enzyme cocktails or explants were used
for UC-MSC harvesting. A similar variation with respect to
the isolation method was also noted in the expression of the
ESC markers c-Kit and Oct-4 by UC-MSCs [36].
WJ-derived UC-MSCs may be Regarded as a Primitive
Stromal Cell Population
Porcine UC-MSCs have been reported to express the
ESC markers Oct-4, Sox-2 and Nanog [37] and equine UC-
MSCs express, apart from Oct-4, the embryonic markers
SSEA4 and c-Kit [38]. In line with these findings, human
UC-MSCs express Oct-4, Nanog, Sox-2, c-Kit, as well as
Dnmt3b and Tert, albeit at lower levels as compared to ESCs
[22, 34, 39]. Such a low expression of the aforementioned
pluripotency markers may explain why UC-MSCs do not
produce teratomas in vivo in immunodeficient mice and rats
[22, 25]. In addition human UC-MSCs express the ESC
markers Tra-1-60, Tra-1-81, SSEA-1 and SSEA-4 [22].
Many of these pluripotent stem cell markers retain their ex-
pression for at least nine passages during ex vivo expansion.
Comparative gene expression profiling between UC-MSCs
and BM-MSCs demonstrated that the former express higher
levels of Nanog, Dnmt3b and Gabrb3, and also
5. 148 Current Stem Cell Research & Therapy, 2013, Vol. 8, No. 2 Batsali et al.
Table 1. Contd….
Markers WJ-derived MSCs Perivascular MSCs BM-MSCs
CD166 ALCAM (activated lymphocyte cell adhesion molecule) + [104] + [5]
CD235 Glyocophorin - [29] - [102]
CD325 N-cadherin + [25] + [102]
HLA-I + [54] + [29] + [110]
HLA- II - [54] - [29] - [110]
HLA G + [34] + [111]
STRO-1
- [81]
+ [112]
+ [113]
SSEA4 Stage-specific embryonic antigen 4 + [105] + [114]
a-SM actin a-smooth muscle actin + [54] - [103] + [10]
NANOG + [25] + [115]
OCT4 + [34] - [29] + [115]
SOX2 + [25] - [6]
GD2 Ganglioside + [26] + [10]
Fig. (2). A scheme depicting the different approaches followed for the establishment of WJ-derived UC-MSC cultures (modified from [100]).
Umbilical cord
Cut tissue into
very small pieces
Dissection in
small segments
Explant culture
Stromal cell culture
Filter
Removal of umbilical
vessels
Scrapping off
mesenchymal tissue
Enzymatic treatment
6. Mesenchymal Stem Cells Derived from Wharton's Jelly Current Stem Cell Research & Therapy, 2013, Vol. 8, No. 2 149
show an increased expression of the pluripotent/stem cell
markers Brix, CD9, Gal, Kit and Rex1 [39]. The implication
of these markers in the biology of UC-MSCs is currently
unknown, yet their expression is thought to reflect the more
primitive nature of UC-MSCs as compared to their adult
counterparts within the BM. However, not all UC-derived
MSCs express ESC markers. In fact, it has been demon-
strated that primitive markers are expressed only by a subset
of UC-MSCs [26, 40], thereby suggesting that these cells are
rather hetereogeneous in terms of stemness. It would there-
fore be very challenging to identify that specific marker
which would permit the isolation of the primi-
tive/multipotent MSCs from UC.
Human UC-MSCs exhibit also higher expression of
genes implicated in the phosphoinositide 3-kinase (PI3K)-
AKT survival/proliferation pathway, including GAB2,
NFKBIA, FOXO1A, YWHAB, FOXO3A, CDKN1A,
MAP3K8, NFKB1, NOS3, DDR1 and TEK [41]. Further-
more, the NF -B pathway has been reported to be more ac-
tive in UC-MSCs than in BM-MSCs [41]. These findings
together with the fact that human WJ-MSCs express the
primitive stem cell marker TERT [25] explain, at least in
part the observation that UC-MSCs have a shorter doubling
time [27] and a more extensive ex vivo expansion capacity
[18].
Multilineage in vitro Differentiation Potential of WJ-
derived UC-MSCs
Accumulating evidence suggests that UC-MSCs can be
successfully induced to differentiate into mesodermal and
non-mesodermal lineages. As mentioned above, several
groups have established that UC-MSCs can generate os-
teoblasts, adipocytes and chondrocytes in vitro [24, 27, 42,
43], thereby fulfilling one of the minimal criteria proposed
by ISCT for MSCs [8]. However, lipid accumulation takes
much longer in UC-MSCs and the adipocytes are less mature
than those derived from BM-MSCs [27, 41]. In addition,
UC-MSCs have been shown to possess weaker osteogenic
[41] and chondrogenic [44, 45] potential as compared to
BM-MSCs.
UC-MSCs have also been reported to successfully differ-
entiate into endothelial cells [43, 46] and actually demon-
strate higher endothelial differentiation potential when com-
pared to BM-MSCs [43]. In accordance with this observation
non-differentiated UC-MSCs exhibit higher expression of
endothelial associated genes including FLT1, GATA4,
GATA6, ISL1, LAMA1, SOX17 and SERPINA1 [39].
One group has suggested, that UC-MSCs can give rise to
skeletal muscle cells when cultured in the appropriate me-
dium and that non-differentiated UC-MSCs may display
myogenic potential in vivo [47]. Differentiation of UC-MSCs
to cardiomyocytes has also been reported but is still contro-
versial [24, 31, 48-50]. For instance, one group [24] demon-
strated that UC-MSCs could be appropriately induced to
form cells demonstrating cardiomyocyte morphology and
expressing cardiac markers, including N-cadherin and car-
diac troponin. Another team [49], however, was unable to
detect cardiomyocyte marker expression after in vitro induc-
tion of MSCs isolated from WJ and perivascular tissues. De-
finitive evidence that UC-MSC-derived cardiomyocytes rep-
resent functional and terminally differentiated cells is still
scarce. To our knowledge, only one group has thus far re-
ported that UC-MSC-derived cardiomyocytes exhibit slight
spontaneous beating after 21 days of induction [31].
Finally, several groups have shown that UC-MSCs can
acquire morphological and biochemical properties of neural
cells when exposed to appropriate differentiation media [27,
32, 51, 52]. Mitchell et al. [32] were the first who observed
UC-MSC neuronal differentiation, following a complex and
multi-step neuronal induction process. Differentiation was
assessed by changes in morphology and expression of neu-
ron specific enolase, bIII-tubulin, neurofilament and tyrosin
hydroxylase. Subsequent studies have further corroborated
these findings. It has also been suggested that UC-MSCs
may be more primed for neuronal differentiation as com-
pared to BM-MSCs, since they express, higher levels of neu-
ronal-associated genes including NESTIN, GFAP and
SEM3A [39] in a non–differentiated state. However, it
should be kept in mind that definitive evidence for electro-
physiological activity of UC-MSC-derived neurons is still
missing. Therefore the issue whether the neuronal-like phe-
notype of UC-MSCs reflects a genuine trans-differentiation
is still pending.
Recent studies suggest that UC-MSCs can also differen-
tiate into endodermal lineages (reviewed in [53]). In this
context, Campard et al. [54] reported that non-differentiated
UCM cells constitutively expressed markers of hepatic line-
age, such as albumin, alpha-fetoprotein, cytokeratin-19, con-
nexin-32, and dipeptidyl peptidase IV. After in vitro hepatic
induction, cells exhibited hepatocyte-like morphology and
upregulated the expression of certain hepatocyte-associated
markers, but lacked important functional properties of ma-
ture liver cells, thereby questioning whether UCM cells have
actually undergone hepatocyte maturation [54]. Other groups
have also claimed that UC-MSCs can be induced to form
isle-like cells [55, 56] (reviewed in [57]), able to express
pancreatic associated genes and release insulin in response to
physiological glucose levels [56]. Interestingly, UC-MSCs
have been reported to have a higher pancreatic differentia-
tion potential than their BM counterparts [55].
The Immunomodulatory Properties of UC-MSCs
Apart from the multilineage potential, UC-MSCs possess
various immunoregulatory properties, rendering them as
appealing candidates for cell based therapies [58]. More pre-
cisely UC-MSCs have been found to exhibit very low ex-
pression of HLA class I, and lack the expression of HLA-DR
[59, 60]. Notably, in comparison to BM-MSCs derived from
aged donors, UC-MSCs express significantly lower levels of
HLA-I, and exhibit significantly higher intracellular concen-
trations of the immunosuppressive molecule HLA-G [59].
These findings together with the observations that UC-MSCs
do not express the co-stimulatory molecules CD40, CD80
and CD86 [59, s61], and do not elicit proliferative responses
from allogeneic T cells in vitro [61], suggest that UC-MSCs
may be characterized by inherently low immunogenicity.
However, another study suggests that UC-MSCs may not be
as immune-privileged as thought, as they can trigger weak
allogeneic immune activation in vitro and will eventually
7. 150 Current Stem Cell Research & Therapy, 2013, Vol. 8, No. 2 Batsali et al.
undergo rejection following xenogeneic transplantation [59].
Similar findings have been reported for BM-MSCs as well.
Interestingly the latter have been shown to be much more
immunocompetent compared to UC-MSCs [59].
Several studies have been published on the immunosup-
pressive potential of UC-MSCs on T lymphocytes [59, 60,
62-64]. One group reported that UC-MSCs target CD4+ and
CD8+ T subpopulations equally and are able to inhibit T-cell
proliferation regardless of the stimulus used to activate T-
cells [63]. Furthermore, UC-MSC-mediated inhibitory ef-
fects were higher than with BM-MSCs. In accordance with
previous studies suggesting that the immunomodulatory ef-
fect of MSCs on T cells may be mediated, at least in part, by
soluble factors (reviewed in [65]), such as hepatocyte growth
factor (HGF), prostaglandin E2 (PGE2), transforming growth
factor- 1 (TGF- 1) and indoleamine 2,3-dioxygenase (IDO),
the authors assessed whether any of these molecules may be
implicated in UC-MSC immunoregulation as well. In their
hands immune suppression exerted by both UC- and BM-
MSCs was mediated by cycloxygenase (COX) 1 and COX2
enzymes, regulating PGE2 synthesis, and by the production
of PGE2 per se, whereas HGF did not seem to be actively
implicated. These findings were further corroborated by an-
other study [64] which additionally showed that while UC-
MSCs intrinsically secrete very low levels of PGE2, its pro-
duction is upregulated when cells are co-cultured in the pres-
ence of activated human peripheral blood mononuclear cells
(hPBMCs). The authors attributed the PGE2 stimulation to
inflammatory cytokines (including IFN- and interleukin-1 )
produced by hPBMCs [64].
Interestingly, several studies [59, 62, 66] have reported
that UC-MSC immune characteristics may be modified fol-
lowing exposure to inflammatory cytokines and/or activated
PBMCs/T-cells so as to display immunosupressive proper-
ties, a process described by the term licensing or priming. In
this context, Deuse et al. [59] reported that IFN- at doses
below 50ng/ml upregulated HLA-DR and HLA-I expression,
thereby increasing UC-MSC immunogenicity. IFN- treat-
ment also induced tolerogenicity by increasing intracellular
HLA-G expression, TGF- and IL-10 release, and stimulated
the production of IDO [59]. Higher doses of IFN- however
enhanced UC-MSC immunosuppressive phenotype by
downregulating HLA-DR expression and further increasing
IDO. These results suggest that appropriate priming may be
crucial for the fine adjustment of MSC characteristics, ren-
dering them suitable for a given therapeutic application.
The immunomodulatory effects of MSCs are not only
apparent in T lymphocytes but also concern B lymphocytes.
To our knowledge however, the impact of UC-MSCs on B
cells has been poorly investigated and undoubtedly awaits
further elucidation, as the information that will be gathered is
expected to provide crucial clues for the introduction of WJ-
MSCs into the clinic. In the single study reported until today
[67] UC-MSCs were found to inhibit B cell proliferation,
differentiation and antibody production in vitro. This sup-
pressive effect is mediated, at least in part by soluble factors,
which may downregulate Blimp-1 and upregualate PAX-5,
two master regulators of B cell differentiation [67]. Further-
more UC-MSCs have been demonstrated to inhibit Akt and
p38 MAPK phosphorylation. Interestingly, these signal
transduction pathways are implicated in the regulation of B
cell proliferation and differentiation [67].
The immunoregulatory potential of HUCPVCs has also
been assessed in a recent study [68]. More precisely it has
been demonstrated that when HUCPVCs are co-cultured
with resting or stimulated allogeneic lymphocytes they fail to
induce their proliferation. Furthermore, HUCPVCs have
been found to reduce in vitro alloreactivity in mixed lym-
phocyte reactions. Notably, the immunosuppressive effect of
the cells is exerted, at least in part via soluble factors [68].
UC-MSCs as Feeder Layers for ex vivo Umbilical Cord
Blood Expansion
Despite the fact that BM has been the most extensively
studied source for HSC transplantation, the importance of
UCB as an alternative source of transplantable HSCs has
been widely acknowledged since the first successful UCB
transplant in 1988 [69]. From a practical point of view UCB
transplantation has several advantages over BM, including
the non-invasiveness of the procedure, the ease of procure-
ment, the reduced risk of transmissible infections and the
availability for immediate use [70]. In addition, UCB grafts
allow for a greater tolerable HLA disparity with a decreased
frequency of acute or chronic graft versus host disease
(GVHD) as compared to BM grafts [70]. Finally UCB con-
tains a higher proportion of immature and committed hema-
topoietic progenitor cells (HPCs) in comparison to adult BM
[71].
However UCB transplantation has also some significant
restrictions, limiting its broad applicability. The most sig-
nificant limiting factor of UCB use is probably the low total
cell dose harvested from a UCB unit, which in turn is associ-
ated with delayed neutrophil and platelet engraftment and
higher engraftment failure [72]. For this reason UCB trans-
plantation remains significantly more successful in children
[73], whereas poor outcomes have been reported in patients
>45 kgr who receive only one unit of UCB [74].
To circumvent these obstacles, so as to improve out-
comes and extend the application of UCB transplantation to
older and/or larger patients, several groups have explored the
possibility of in vivo expansion of HSCs from UCB units.
Various protocols are under investigation over the last 30
years, including those based on cultures on feeder layers.
Among the different cell types that have been used as stro-
mal support for UCB expansion, the most extensively stud-
ied thus far are BM- MSCs.
The rationale behind the use of MSCs as feeder cells for
UCB expansion lies on a large body of evidence, clearly
demonstrating the BM-MSC promoting role on hematopoie-
sis (reviewed in [65]). More precisely BM-MSCs have been
shown in vivo to enhance HSC engraftment and repopula-
tion, as evidenced by the observation that co-transplantation
of human HSCs and MSCs results in increased chimerism
and/or hematopoietic recovery, in both animal models and
humans [65, 75]. On the other hand, MSCs have been shown
in vitro to maintain long-term culture initiating cells (LT-
CICs) and expand lineage-specific colony forming units
from CD34+
marrow cells in long-term BM cultures (re-
viewed in [65]). Even though the exact mechanisms that me-
8. Mesenchymal Stem Cells Derived from Wharton's Jelly Current Stem Cell Research & Therapy, 2013, Vol. 8, No. 2 151
diate the hematopoiesis promoting effect of MSCs have not
been elucidated, it is now widely accepted that MSCs supply
HSCs and their progeny with signals for survival, prolifera-
tion and differentiation through direct cell-to-cell contact
and/or production of cytokines, adhesion molecules and ex-
tracellular matrix proteins (reviewed in [65]).
These observations have provided the theoretical back-
ground for the investigation of the potential use of MSCs as
scaffolds for the ex vivo expansion of HSCs. Based on the
hypothesis that MSCs could provide many of the molecular
cues of the hematopoietic microenvironment necessary to
favor HSC self-renewal and regulate their proliferation, CB
hematopoetic stem/progenitor cells have been co-cultured on
BM-MSC preformed layers in a medium containing (FBS)
and various combinations of growth factors including G-
CSF, stem cell factor (SCF), thrombopoietin (TPO), Flt3-
ligand or fibroblast growth factor-1 (FGF-1) [76]. Using this
ex vivo model several groups have demonstrated an increase
in the number of total nucleated cells (TNC), clonogenic
cells or CD34+
cells [77, 78]. These findings were further
corroborated in a recent study [79], where CB CD34+
cells
were co-cultured with BM-MSCs in a serum free medium
supplemented with SCF, TPO and FGF-1. BM-MSCs were
also shown to maintain the primitive phenotype of CB hema-
topoietic stem and progenitor cells even after massive expan-
sion [79]. However co-culture with BM-MSCs did not result
in a significant expansion of long-term repopulating cells. A
clinical trial is underway at M.D. Anderson Cancer Center
combining an unmanipulated UCB unit with an expanded
UCB unit for 14 days in the presence of a cytokine cocktail
on layer of family member donor-derived BM-MSCs or "off-
the-self" BM-MSCs (Angioblast Systems Inc.). Preliminary
results suggest a beneficial role for these stromal cell-based
HSC expansion [80].
Given the promising role of BM-MSCs in supporting ex
vivo UCB expansion and since UC-MSCs share many char-
acteristics with their BM counterparts, but in contrast to the
latter can be readily and painlessly harvested from UC, they
soon emerged as attractive candidates for HSC expansion. In
this regard, the first report demonstrating that akin to BM-
MSCs, UC-MSCs can also support hematopoiesis was pub-
lished in 2007 [81]. In that study the authors showed that
UC-MSCs secrete significantly higher amounts of several
important cytokines and hematopoietic growth factors in-
cluding G-CSF, GM-CSF, LIF, IL-1 , L-6, IL-8 and IL-11,
compared to BM-MSCs. Furthemore co-culture of UC-
MSCs with UCB CD34+
cells significantly increased hema-
topoietic colony formation as compared to clonogenic pro-
genitor cell assays performed in the absence of MSCs [81].
Finally, in agreement with previous reports demonstrating
that co-transplantation of BM-MSCs with HSCs can acceler-
ate hematopoietic engraftment, co-injection of UC-MSCs
with UCB cells or CD34+
cells in a NOD/SCID mouse
model accelerated human HSC recovery. The authors as-
sumed that the improved engraftment might be attributed to
the presence of UC- MSCs within the BM of the recipient
animals and also to the production of hematopoietic cytoki-
nes by these cells. Subsequent reports have confirmed the
capacity of UC-MSCs and UC-MSC conditioned medium to
support the growth and maintenance of UCB hematopoietic
stem/progenitor cells in long term culture [82, 83], thereby
establishing an ex vivo model that could enable the study of
the interactions between HSCs and their supportive micro-
environment within the UC. However, whether UC MSC-
based HSC expansion will have possible future clinical util-
ity is currently unknown and awaits further clarification.
UC-MSCs for GVHD Treatment
Graft versus host disease (GVHD) is one of the most
severe complications of allogeneic BM transplantation. First-
line treatment with corticosteroids is the gold standard for
this T-cell mediated process, however second line treatment
for steroid-resistant GVHD has not been clearly established
thus far and the outcome is poor, with one year overall sur-
vival (OS) of only 30% [84, 85].
The in vitro and in vivo immunomodulatory properties of
BM-MSCs have provided the theoretical background for the
use of these cells for treatment of acute steroid-resistant
GVHD. Several reports have been published thus far (re-
viewed in [86]) suggesting that clinical responses can actu-
ally be attained in a significant number of patients, especially
in children. BM-MSCs have also been used for the treatment
of chronic GVHD showing likewise promising results [86].
To our knowledge, there has been only one recent study
clinically testing UC- MSCs for GVHD [87]. In that particu-
lar report third-party culture expanded UC- MSCs were
transplanted in 2 children with severe steroid-resistant acute
GVHD. The first patient received three infusions of UC-
MSCs. Each time acute GVHD improved significantly and
eventually disappeared. The second patient received only
one infusion of UC-MSCs that led to complete remission of
acute GVHD. No child experienced any adverse events what
so ever and both children were well and remained off immu-
nosuppressive therapy at the time the study was published.
The authors concluded that UC-MSCs may be considered as
a feasible, safe and effective treatment modality for acute
GVHD [87]. These encouraging results need obviously to be
confirmed by larger trials, which will include adult patients
as well. Furthermore, additional studies are needed in order
to optimize the use of UC-MSCs in treating GVHD. For ex-
ample, it is currently unknown which is the optimal UC-
MSC dose and schedule, or whether the use of platelet-
lysate, or other substitutes of the standard FBS-enriched me-
dium (so as to comply with regulatory guidelines for the
production of MSCs for clinical use, which recommend
avoiding the use of animal derivatives) might influence the
therapeutic effect of UC-MSCs.
UC-MSCs Support the Expansion of Natural Killer Cells
As previously mentioned a major toxicity associated with
Bone Marrow Transplantation (BMT) is GVHD, an attack
by the T cells in the graft against the recipient organs includ-
ing the skin, gastrointestinal tract, liver, and eyes [88]. Ag-
gressive depletion of T cells in the allogeneic graft can
markedly reduce the incidence of acute GVHD, however,
this is associated with significant drawbacks, including re-
duction of the graft versus tumor effect of the allogeneic-
BMT [89]. Limiting therefore GVHD while maintaining the
9. 152 Current Stem Cell Research & Therapy, 2013, Vol. 8, No. 2 Batsali et al.
antitumor effect, would be critical to improve transplant out-
come [90]. Given that natural killer (NK) cells have been
found to control leukemia relapse while protecting patients
from GVHD [91, 92], the possibility of expanding and po-
tentially using these cells for adoptive immunotherapy ap-
pears an attractive approach in the setting of allogeneic
BMT. Provided that UCB is rich in NK cell progenitors and
since UC-MSCs can produce significant amounts of cytoki-
nes, Boissel et al. [93] hypothesized that a feeder layer of
UC-MSCs might actually effectively support ex vivo expan-
sion of UCB-NK cells. Indeed when CD3-depleted UCB
mononuclear cells were cocultured with UC-MSCs and a
cytokine cocktail, the proportion of CD3-
CD56+
NK cells
increased significantly as compared to cell cultured with
cytokines only. Interestingly direct contact between UCB
mononuclear cells and UC-MSCs resulted in a significantly
greater NK cell expansion. Notably, expanded NK cells
maintained an elevated cytotoxic profile [93]. The possibility
of further optimizing this experimental protocol should be
evaluated in additional studies and of course the cytotoxicity
of the expanded NK cells awaits assessment in animal mod-
els.
UC-MSC Transplantation in Systemic Lupus Erythema-
tosus
To our knowledge, apart from GVHD, in vivo therapeutic
efficacy of UC- MSC transplantation has also been clearly
illustrated in the setting of systemic lupus erythematosus
(SLE). The theoretical background for assessing the clinical
impact of UC-MSCs in patients with this autoimmune disor-
der has been provided by the immunomodulatory properties
of UC-MSCs and also by the beneficial effects of BM- MSC
administration in patients with treatment-refractory SLE
[94]. In this context, it has recently been reported that trans-
plantation of UC-MSCs in patients with severe and refrac-
tory SLE results in clinical and serologic improvement and is
not associated with mortality or other treatment-related ad-
verse events [95]. Even though the mechanisms mediating
the therapeutic effect of UC-MSCs in SLE patients remain
unclear, it has been suggested that disease remission may be
associated with an increase in the proportion of Tregs in pe-
ripheral blood along with a decrease in IL-4 serum levels,
probably resulting in inhibition of humoral activity [95].
Another recent study has demonstrated that UC-MSCs can
also provide clinical benefit in diffuse alveolar hemorrhage,
a rare complication of SLE with high clinical mortality [96].
These findings suggest that UC-MSC transplantation may
hold promise as a treatment modality in selected SLE cases.
However, the efficacy and safety of this strategy need to be
further validated in larger clinical trials with longer periods
of follow-up.
Therapeutic Potential of UC-MSCs in Cancer
An emerging clinical application of UC-MSCs that re-
cently gained much attention is their use as cellular therapy
to combat cancer. One group has thus administered UC-
MSCs engineered to secrete interferon- , in combination
with low-dose intraperitoneal injections of 5-fluorouracil in
severe combined immunodeficiency (SCID) mice, bearing
human breast carcinoma tumors in their lungs [97]. Inter-
estingly, UC-MSCs were only found in the lungs and not in
other tissues. This combined approach resulted in significant
metastatic tumor reduction, much greater than compared to
each treatment alone. A more recent study has corroborated
the ability of UC-MSCs to reduce the growth of human
breast carcinoma cells both in vitro as well as in vivo, in a
mouse xenograft model [98]. Notably, the antitumor proper-
ties of UC-MSCs do not seem to be specific only to breast
cancer cells, but have also been demonstrated in osteosar-
coma and ovarian carcinoma cell lines in vitro [99]. The
mechanisms mediating UC-MSC anticancer effects are still
under investigation. However, it has been suggested that UC-
MSCs exert their antitumor activity both via cell-to-cell con-
tact and humoral factors, through induction of apoptosis, cell
cycle arrest and autophagy [97, 99]. Taken together, the
aforementioned preliminary data imply that UC-MSCs may
hold promise as a therapeutic modality in cancer and high-
light the need for the development of additional well-
designed pre-clinical studies so as to properly investigate the
potential of this cell-based approach.
CONCLUSION
Within recent years considerable interest has been given
to the exciting properties of UC-MSCs, derived from the WJ,
because of their primitive nature as compared to BM-MSCs
(the prototype of adult MSCs), their multilineage potential
across germ layers, the extensive in vitro proliferation and
their immunosuppressive capacity. These characteristics
along with the ease by which UC-MSCs are isolated from a
tissue with unlimited availability, have generated much en-
thusiasm regarding their potential applications in cell-based
therapies. This expectation is being supported by both pre-
and clinical data. In particular, in this review we reported on
the promising results obtained in recent studies regarding the
use of UC-MSCs for the treatment of cancer and immune
mediated disorders, such as graft versus host disease and
systemic lupus erythematosus and discussed UC-MSC role
as feeder layers for ex vivo HSC expansion. Nevertheless
much work has to be done so as to fully unravel the biologic
features of UC-MSCs and especially those distinguishing
them from adult MSCs. Furthermore, properly designed
comparative studies need to be undertaken in the near future
so as to clearly identify and characterize MSC subpopula-
tions originating from different regions of WJ, in order to
answer the long-standing question: whether different ana-
tomical locations within WJ are associated with distinct
qualitative and quantitative MSC properties. Notably, avail-
able global expression technologies, like gene expression
and comparative genomic hybridization (CGH) microarrays,
proteome and secretome profiles, methylation mapping and
ChIP-on-ChiP technologies are anticipated to contribute sig-
nificantly to the better understanding of UC-MSC biology. It
is anticipated that the data obtained by these studies will not
only provide the theoretical background for the eventual in-
troduction of UC-MSCs in the clinic, but would also be ma-
jor contribution to stem cell biology in general.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flicts of interest.
10. Mesenchymal Stem Cells Derived from Wharton's Jelly Current Stem Cell Research & Therapy, 2013, Vol. 8, No. 2 153
ACKNOWLEDGEMENTS
Declared none.
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Received: October 16, 2012 Revised: December 17, 2012 Accepted: December 28, 2012