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.
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.
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.
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/
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 ...
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.
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.
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.
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/
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 ...
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.
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.
Potential Diagnostic Biomarkers for Human Uterine Mesenchymal Tumours Especia...ijtsrd
Aims Although the majority of smooth muscle neoplasms found in the uterus are benign, uterine leiomyosarcoma is extremely malignant, with high rates of recurrence and metastasis. The development of gynecologic tumors is often correlated with secretion of female hormone however, the development of human uterine leiomyosarcoma is not substantially correlated with hormonal conditions, and the risk factors are unclearly understood. Importantly, a diagnostic biomarker, which distinguishes malignant human uterine leiomyosarcoma from benign tumor leiomyoma is yet to be established. It is necessary to analyze risk factors associated with human uterine leiomyosarcoma, in order to establish a diagnostic biomarker and a clinical treatment method. Methodology Histology and Immunofluorescence Staining tissue sections 5 µm were prepared and stained with HandE for routine histological examination or were processed further for immunofluorescence staining with appropriate antibodies. Furthermore, a total of 57 patients between 32 and 83 years of age and diagnosed as having smooth muscle tumors of the uterus were selected from pathological files. Immunohistochemistry staining for LMP2 1i and cyclin E1 was performed on serial human uterine leiomyosarcoma, leiomyoma and myometrium sections. Results Homozygous deficient mice for a proteasome subunit LMP2 1i spontaneously develop uterine leiomyosarcoma, with a disease prevalence of ~40 by 14 months of age. Defective LMP2 1i and cyclin E1 positive expressions in human uterine leiomyosarcoma were demonstrated, but the reverse result was obtained in human leiomyoma and myometrium. Conclusions LMP2 1i and cyclin E1 differential expressions may be one of the risk factors for human uterine leiomyosarcoma. LMP2 1i and cyclin E1 may be potential diagnostic biomarker and targeted molecule for a new therapeutic approach. Takuma Hayashi | Hiroyuki Aburatani | Ikuo Konishi "Potential Diagnostic Biomarkers for Human Uterine Mesenchymal Tumours: Especially LMP2/1i and Cyclin E1-Differential Expressions" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-8 | Issue-1 , February 2024, URL: https://www.ijtsrd.com/papers/ijtsrd62380.pdf Paper Url: https://www.ijtsrd.com/medicine/other/62380/potential-diagnostic-biomarkers-for-human-uterine-mesenchymal-tumours-especially-lmp21i-and-cyclin-e1differential-expressions/takuma-hayashi
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/
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.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
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.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
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.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
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.
2. childbirth through umbilical vein. All of those cells have the advantage of being defined as “young” stem cells, and
despite their primitive character, they can be isolated without ethical concerns, as developed from extraembryonic
tissues. Moreover, those cells are acquired from medical waste after delivery and are not connected with invasive and
painful procedures. However, differences between cells obtained from separate compartments were noted, which may
suggest their distinct origin [9,10]. Among those cells, WJ-MSCs have been marked as most feasible for cellular
therapies. Ease of isolation, high yield, purity and proliferation rate make them attractive source for transplantation
procedures.
WJ is an extracellular matrix (ECM) proteinerich compartment of UC, which is composed of collagens, glycos-
aminoglycans, and hyaluronic acid [11]. Main role of such structure is to protect UC vessels from pressure, bending,
and torsions during pregnancy. Enriched ECM is also great “storage” of growth factors such as acidic and
basic fibroblast growth factors (aFGF, bFGF), epidermal growth factors (EGF), insulin-like growth factor 1 (IGF-1),
platelet-derived growth factor (PDGF), and transforming growth factor beta (TGF-b) that can support dispersed stromal
cells [12].
There are two possibilities how MSCs are populating WJ. First one claims that during fetal MSCs migrations during
development, a portion of cells can be trapped in WJ [13]. Second theory postulates that MSCs can originate
from primitive mesoderm that is present in the UC from the beginning, where their key role is to produce matrix
proteins [14].
(A) (B)
(C)
FIGURE 21.1 Photography of human umbilical cord (UC) (A). Schematic cross section of human UC (B). Microphotography of in vitro cultured WJ-
MSCs. Magnitude 100Â.White bar represents 100 mm (C).
282 SECTION j III Umbilical CordeDerived Cells
3. WJ-MSCs can be isolated from WJ enzymatically by collagenase, trypsin, hyaluronidase, or mixture of them. They can
also migrate directly from UC explants. Importantly, depending on chosen isolation method, cells can slightly differ in
features such as expression of pluripotency markers and cell proliferation rates [15].
WJ-MSC FEATURES
Important drawbacks of using adult stem cells include their naturally low number, difficulties with harvesting, and low
expansion potential. Stem cells harvested from perinatal tissues (such as cord blood, amniotic fluid, and cord) possess
several attractive characteristics that resemble those of embryonic stem cells in absence of the embryonic stem cells
disadvantages. Today, the most studied type of perinatal stem cells are hematopoietic stem cells isolated from cord blood
during delivery. Cells from the cord, however, are still underevaluated and thus underappreciated.
WJ-MSCs share common characteristics with MSCs isolated from other sources, such as adult bone marrow (BM-
MSCs) and adipose tissues (AT-MSCs). They are adherent, fibroblast-like cells, and as no separate specific marker for
MSCs has been yet described, International Society for Cellular Therapy established a gold standard panel of surface
markers to describe their phenotype [16]. Cultured MSCs are defined as cells positive for CD73, CD90, CD105 (all >95%)
and negative for CD34, CD45, CD11b/integrin alpha M or CD14, CD79 alpha or CD19, HLA class II (all <2%).
However, the latter markers can change when MSCs are exposed to inflammatory cytokines [17]. Yet, because of absence
of costimulatory CD80, CD86, CD134, CD252, MSCs are unable to induce T cell activation [17]. Moreover, when
cultured in vitro, they can also differentiate to adipocytes, chondrocytes, and osteocytes. WJ-MSCs are also capable to
transdifferentiate in vitro to cells outside mesenchymal lineages, such as cardiomyocytes, endothelial cells, and cells from
neuronal lineage [8,18], which suggests their broader-than-multipotent potential.
Yet, thanks to their origin, WJ-MSCs are presented as “young” or primitive cells in comparison with MSCs isolated
from adult sources and have superior biological properties. WJ-MSCs demonstrate features intermediate between ESCs
and adult MSCs because of expression of POUF1, SOX2, NANOG, LIN28, SSEA1, SSEA3, SSEA4, KLF4, c-MYC,
CRIPTO, and REX1 [19,20]. However, distinct lower expression of pluripotent genes in comparison with hESCs may be a
reason why WJ-MSCs do not form teratomas when transplanted to immune-deficient mice [21]. Unlike BM-MSCs, WJ-
MSCs are not able to transform to tumor-associated fibroblasts (TAFs) phenotype, when exposed in vitro to breast or
ovarian cancereconditioned media [22]. Furthermore, WJ-MSCs display anticancer properties, as shown as elevated
expression of IL-12 or cancer growth inhibition in xenograft model [20,23].
Accordingly, thanks to origin of WJ-MSCs, these cells have profound immune tolerance and are even called hypo-
immunogenic cells. Physiologically, it may be related to their presence in the UC and prevention of fetus rejection. It is
based on secretion of a variety of factors, e.g., HLA-G and CD274 [17]. Notably, high expression levels of HLA-G6 are a
unique feature of WJ-MSCs [24]. It was also shown that WJ-MSCs have the lowest expression of HLA-DR even in
immune-primed conditions among MSCs [25]. Also, WJ-MSCs can secrete higher levels of hepatocyte growth factor
(HGF), prostaglandin E2 (PGE2), and decreased amount of insulin-like growth factorebinding protein-3 (IGFB3) because
of inflammatory cytokines stimulation [17]. Moreover, WJ-MSCs can diminish immune responses by secreting key
regulatory factors such as IL-10, TGF-b, IL-6, vascular endothelial growth factor (VEGF), indoleamine 2, 3-dioxygenase
(IDO), and B7eH1 [24,26e28]. WJ-MSCs were also shown to uniquely secrete IL-12, IL-15, and PDGF-AA [26].
Functionally, WJ-MSCs can greatly suppress allogeneically stimulated T lymphocytes and inhibit maturation and acti-
vation of dendritic cells (DCs) [26,28].
Substantial immune tolerance plays a crucial role in choosing WJ-MSCs as a perfect source for allogeneic trans-
plantations, especially in acute cardiovascular disorders when transplantation is needed immediately after occurrence of
injury because of lack of time for propagation of autologous MSCs. Allogeneic transplantation also solves problems of
limited amount of autologous MSCs or their altered phenotype because of CVDs’ co-morbidities [29]. However, it is
noteworthy that detailed analysis of mother’s health is needed, as conditions such as diabetes can influence WJ-MSCs’
performance [30].
WJ-MSCs in comparison with other MSCs express key early cardiac transcription factors, such as Flk-1, Isl-1, Nkx2.5,
GATA-4, GATA-5, and GATA-6, which can be significant for therapies of CVDs [19,31]. WJ-MSCs can secrete a
plethora of factors, which were reviewed elsewhere, and their secretome was analyzed in comparison with other sources
[32e34]. Briefly, WJ-MSCs secrete many proangiogenic factors such as VEGF, HGF, angiopoietin and TGF-b1, that are
critical for cardiac remodeling and progression after heart failure and can also influence resident cardiac stem cells [32,35].
However, BM-MSCs and AT-MSCs were shown to have more profound proangiogenic character [32]. WJ-MSCs have
high expression of CD54 and CD146dadhesion molecules that are related to their migratory character.
Wharton’s Jelly MSC and Cardiovascular Damage Chapter | 21 283
4. WJ-MSCs can also differentiate into cardiomyocytes by use of 5-azacytidine, oxytocin or through “embryoid body”
formation [36]. However, oxytocin seems to be a more potent inducer of differentiation, which is consistent with the fact
that this peptide is highly expressed in the developing heart [37]. Differentiation of WJ-MSCs can be assessed by
expression of cardiac troponins, connexin 43, as well as changes in morphology. However, the differentiation of WJ-MSCs
to cardiomyocytes in vivo is still debatable, as paracrine effect of these cells has a profound regenerative potential [38].
WJ-MSCS IN PRECLINICAL TRIALS
There are numerous reports proving highly beneficial effects of BM-MSC transplantation in animal models of CVDs
[39e45]. However, there are as many limitations of their use, which involve, but are not restricted to, invasiveness of
acquisition, age of donor, limited cell number. WJ-MSCs possess unique features that make them ideal candidates for
regenerative therapies of the heart, even among MSCs of different origin.
WJ-MSCs, like other MSCs, have the potential to differentiate into key cells lost in heart infarction d cardiomyocytes.
WJ-MSCs treated in vitro with 5-azacytidine- or cardiomyocyte-conditioned medium expressed cardiomyocyte markers,
namely, N-cadherin and cardiac troponin I [8], suggesting cardiac differentiation. This ability was also observed for
perivascular MSCs in the UC [46] but interestingly not for UC blood cells [47,48].
WJ-MSCs were shown to be capable of cardiac function improvement in the rat model of myocardial infarction [49].
WJ-MSCs injected into infarcted regions survived for as long as 4 weeks and were found around arterioles and scattered in
capillary networks. Transplanted cells expressed cardiac troponin-T, von Willebrand factor, and smooth muscle actin,
indicating that multilineage differentiation of WJ-MSCs d into cardiomyocytes, endothelial cells, and smooth muscle cells
d takes place during regeneration of ischemic myocardium. More importantly, parameters of the heart improved upon WJ-
MSC transplantation. Left ventricular ejection fraction (LVEF) and left ventricular posterior wall thickness improved, with
a decrease in apoptotic cells [49]. Moreover, capillary and arteriole density increased compared with the control group,
confirming the angiogenic potential of WJ-MSCs. It was previously shown that WJ-MSCs can differentiate into endothelial
cells expressing endothelial-specific proteins, such as platelet endothelial cell adhesion molecule, PECAM, and CD34 both
in vitro (when stimulated with VEGF and bFGF) and in vivo (endothelial cells sprouting from local injection in a hindlimb
ischemia mouse model) [50]. What is noteworthy is that similarly beneficial effects delivered by UC perivascular cells [46]
increased cardiac function in murine model of acute myocardial infarction 14 days after transplantation.
Several weeks may seem to be not long enough for drawing unambiguous conclusions concerning efficacy of WJ-
MSCs transplantation; nevertheless, WJ-MSCs were also proved to have long-term beneficial effects on infarcted heart
in rat model [51]. Intravenous injection of WJ-MSCs proved not only homing capacity of these cells toward injured
sites (cells were found in periinfarction regions) but also significant capacity for prolonged improvement in ejection
fraction. These improvements were observed in treated animals for at least 31 weeks. Homing and integration of WJ-MSCs
with cardiac tissue were also described previously [52]. WJ-MSCs were markedly chemoattracted toward the embryonic
murine ventricular slices and were able to integrate robustly into the depth of both living and ischemic cardiac tissues
in vitro.
Another study showed that WJ-MSCs injected into murine heart directly after myocardial infarction induced by left
anterior descending coronary artery ligation preserved heart function and attenuated cardiac remodeling process, evaluated
2 weeks after the infarction. They also stimulated angiogenesis that increased capillary density; however, there were no
differences in infarct size upon cells transplantation. Apoptosis in the infarcted tissue was also prevented. Moreover,
WJ-MSC-conditioned medium was able to enhance cellular vasculogenesis and activate cardiomyogenic gene expression
program in vitro, proving strong paracrine activity of WJ-MSCs [53].
Many studies suggest that WJ-MSCs tend to be superior to BM-MSCs. They are able to efficiently differentiate toward
functional cardiomyocytes and form myotube structures capable of spontaneous contractions in vitro after coculture with
fetal MSCs but not with adult MSCs (like BM-MSCs) [51]. UC perivascular stem cells exceeded BM-MSCs in cardiac
differentiation potential and beneficial influence on infarcted heart [46]. This phenomenon suggests that “young” (peri-
natal) stem cells possess more profound differentiation potential and as such can be a more powerful tool for regenerative
cell therapy than “old” (adult) stem cells.
Cell transplantations in small animal models (mice and rats) are vital for deciphering mechanisms of MSC actions in
cardiac regenerations. However, experiments on large animal models (such as dogs and pigs) are crucial for closing the gap
between research and clinical utility, as their size, anatomy, and physiology are similar to human.
WJ-MSCs were proved to be efficient in a mini-swine acute myocardial infarction model [54]. Transplanted cells
significantly improved myocardial perfusion and function of the infarcted area in the left ventricle. WJ-MSCs efficiently
engrafted and differentiated into cardiomyocytes and vascular endothelium in 6 weeks after transplantation. They also
284 SECTION j III Umbilical CordeDerived Cells
5. increased vascular density, viable myocardium size, and reduced apoptosis. It is also noteworthy that transplanted
WJ-MSCs promoted recruitment and differentiation of resident cardiac stem cells, proving the important role of cellecell
communication in MSCs regenerative mechanisms (Fig. 21.2).
Another approach for potential future cell therapy of CVDs is tissue engineering. Stem cells isolated from different
regions of UC can be seeded on biocompatible 3D scaffolds for expansion, differentiation, and generation of “patches”
placed in/on damaged tissues [55]. An example of such an approach is artificially engineered pulmonary valves created by
seeding endothelial cells onto synthetic biodegradable scaffold consisting of polyglycolic acid fibers [56]. WJ-MSCs can
be used to create a myocardial patch, which can be helpful in regeneration of infarcted muscle [57]. Biodegradable
macroporous tubes, which allow transport of growth media into the construct, were populated with WJ-MSCs, which
expressed high viability, uniform cell distribution, and alignment due to nutrient provision within bioreactor [57]. Cells
seeded on similar scaffolds can be differentiated toward cardiomyocytes in vitro. Such 3D constructs have a potential to
mimic the structure of the native myocardium and can be used to “patch” a damaged region in infarcted heart.
Although results in preclinical studies are very promising, showing improvement in widely defined cardiac function
(increased ejection fraction, decrease in scar tissue, reversed remodeling, improved contractility, reduced apoptosis,
augmented heart perfusion, and blood vessel density), long-term assessment of WJ-MSCs’ safety and efficacy is still
needed.
WJ-MSCS IN CLINICAL TRIALS
Easily achievable (e.g., off-the-shelf) and highly effective cell type for cell replacement therapy is yet to be determined. For
instance, the embryonic stem cells or induced pluripotent stem cells are also usable sources of cells for regenerative
medicine. Use of these cells, however, is associated with several ethical and technical problems. Another way to obtain
stem cells for regenerative medicine is their isolation from somatic tissues.
FIGURE 21.2 Mechanism of action of mesenchymal stem cells in cardiovascular diseases. Modified from Servier Medical Art.
Wharton’s Jelly MSC and Cardiovascular Damage Chapter | 21 285
6. The key characteristics of WJ-MSCs are their multipotent properties - laying somewhere between pluripotent
embryonic stem cells and unipotent adult stem cells [14]. WJ-MSCs have higher proliferation rates and self-renewal
capacity compared with adult stem cells [9]. The overall evidence indicates that under appropriate vigilance, including
cytogenetic screening [58] such as implemented in the CIRCULATE project, human WJ-MSCs can be safely introduced
in clinical use.
In essence, human WJ-MSCs are allogeneic but nonimmunogenic, when transplanted into another human. Wharton’s
Jelly is also a very promising source of MSCs for clinical application in acute myocardial infarction. WJ-MSCs have been
shown to be safe and beneficial in two independent studies [59,60], with a suggestion of the beneficial effect on infarct size
and left ventricular contractility [60].
With Ethics Committee approval, we have demonstrated safety and feasibility of WJ-MSCs application to treat human
myocardium [59]. In addition, using state-of-the-art imaging techniques [61], we have demonstrated that myocardial
ischemic tissue uptake of WJ-MSCs is 5- to 6-fold greater than that of CD34 cells [62].
In the second study, Gao and coworkers performed double-blinded, randomized controlled multicenter trials.
They showed safety and feasibility of this approach. Monitoring of patients during the 18-month follow-up
demonstrated increase in the myocardial viability and left ventricular ejection fraction (LVEF) in the group transplanted
with WJ-MSCs [60].
Based on the already demonstrated regenerative potential of MSCs, encouraging data from published preclinical
studies, and clinical safety and feasibility work, we propose a novel approach for the ischemic tissue regeneration of
important civilization diseases, including acute myocardial infarction, chronic ischemic myocardial injury, and lower limb
ischemia d an approach based on WJ-MSC allogeneic transplantation.
This novel approach is based on obtaining MSCs from an “unlimited” source, noninvasive and low cost (in comparison
with iPS cells or expansion of autologous bone marrow cells) d Wharton’s Jelly d creating an allogeneic cell bank based
on which an “off-the-shelf” cell therapy product which could be used immediately, providing sufficient number of the cells
for the treatment of a variety of diseases. This treatment strategy, using human WJ-MSCs as a tool to regenerate or
stimulate the regeneration of the damaged tissues, will not only lead to life saving treatments but also enhance their quality
of life. Thus, in the long run, the proposed approach not only will increase the effectiveness of medical treatment (acute and
chronic myocardial disorders) but also may provide the first effective treatment (e.g., in no-option limbs ischemia). This
would bring a new era in the treatment modalities and, in consequence, enormous savings in spending on the hospitali-
zation and social benefitebased care.
CONCLUSIONS
WJ-MSCs possess a number of features, which make them an ideal candidate for future regenerative therapy in CVDs.
Their immunoprivilege ensures histocompatibility and crosses transplant rejection risk out of the equation. As they are not
tumorigenic, their safety is considerably higher than pluripotent cells, which, even after differentiation, remain as a “ticking
bomb” within the patient’s body. WJ-MSCs’ secretion potential guarantees their strong pleiotropic effect on infarcted
heart, not only in resolution of inflammation in infarcted heart, but also in preparation of injured niche for cell homing.
Because they are capable of specific homing into injured sites, their application can be noninvasive (e.g., intravenous). As
WJ-MSCs are capable of cardiac and endothelial differentiation, they are a promising source of cells, which are essential
for repairing infarcted heart. Furthermore, their acquisition (unlike liposuction or bone marrow aspiration) is pain free and
generates abundant perinatal cells. Their ease of allogeneic use makes them an ideal candidate for off-the-shelf products for
personalized therapy in CVDs immediately after infarction (often not feasible in case of autologous cells), time which
sometimes can be life saving. Our group works on preparation of WJ-MSCs as an allogeneic medical agent in the
CIRCULATE project for both preclinical and clinical trials [59]. This approach can close the gap of unmet needs
concerning MSC clinical applications which involves, but are not restricted to, poor availability of abundant autologous
cells in a short period of time after heart failure. It is estimated that approximately 109
cells die in heart attack, which is the
order of magnitude necessary for transplantation within days after heart incident. Allogeneic “off-the-shelf” approaches
appears to be more feasible than autologous cell expansion.
Moreover, because cardiovascular disorders concern mainly elderly people with co-morbidities (e.g., diabetes), it is safe
to assume that their autologous cells would also suffer “co-morbidities,” which can diminish long-term therapeutic effect of
transplanted autologous cells. This risk is overcome by application of “young and healthy” allogeneic cells.
286 SECTION j III Umbilical CordeDerived Cells
7. WJ-MSCs’ features make them extremely promising cells for future regenerative therapy in cardiovascular disorders.
However, there is still a demand for large comprehensive, randomized, controlled trials that establishes crucial features of
MSC in CVDs (e.g., number of cells, time and method of application). Nevertheless, the future for perinatal cells in
regenerative medicine is bright.
ACKNOWLEDGMENT
This work was supported by research grant (Strategmed2/ 265761/10/NCBR/2015) from the National Center for Research and Development.
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