The document discusses stem cells, their types, properties, and applications in tissue renewal and regeneration, focusing on embryonic and adult stem cells. It elaborates on mesenchymal stem cells (MSCs), their sources, immunomodulatory advantages, and tissue engineering strategies, highlighting their role in treating conditions like knee osteoarthritis and spinal cord injuries. The conclusion emphasizes the promising outcomes of stem cell treatments while acknowledging the ongoing research and challenges in the field.

1. Stem Cell and Tissue
Renewal
Supervisor:
Prof. Dr. dr. Ismail Hadisoebroto Dilogo, SpOT(K)
Presentan
Aslambotilangih

2. Stem Cell / Sel Punca
• unspecialized
• self renewal
• can be induced to form specific cell types

3. 1 stem cell
Self renewal -
maintains the stem cell
pool
4 specialized cells
Differentiation replaces dead or damaged
cells throught the life
Why self-renew AND differentiate?
1 stem cell

4. Properties of stem cell
Clonogenic, a single ES cell gives rise to a colony of genetically identical cells, which have
the same properties as the original cell
Expresses the transcription factor Oct-4 Can be induced to continue
proliferating or to differentiate
Lacks the G1 checkpoint in the cell cycle
ES cells spend most of their life cycle in S phase
Don’t show X inactivation

5. Types of Stem Cells based on potential
Stem cell
type Description
Examples
Totipotent
Each cell can develop
into a new individual
Pluripotent
Pluripotent
Cells can form any
(over 200) cell types
Multipotent
Cells differentiated,
but can form a number
of other tissues
Cells from early
(1-3 days)
embryos
Some cells of
blastocyst (5 to
14 days)
Fetal tissue, cord
blood, and adult
stem cells

6. Types of Stem Cell
- Embryonal stem
cells
- Adult stem cells
- Mesenchymal stem
cells
- Hematopoietic
stem cells

7. Embryonal stem cells
1. Derived from the blastocyst, which is made up of an outer layer of cells
(the trophectoderm), a fluid ectoderm filled cavity (the blastocoele), and
a cluster of cells on the interior.
2. The ICM, which contains the ES cells must first be isolated from the
surrounding trophoblast cells
3. Capable of self-renewal and differentiation into cells of all tissue lineages,
and they have the capacity for exceptionally prolonged culture (1–2 years
with cell division every 36–48 hours)
4. ES cells are difficult to derive and maintain in culture

8. Adult Stem Cells (Somatic Stem Cell):
Definition: Undifferentiated cells found living within specific differentiated tissues in
our bodies that can renew themselves or generate new cells that can replenish
dead or damaged tissue
Types of Adult Stem Cells:
Hematopoietic Stem Cells (Blood Stem Cells)
Mesenchymal Stem Cells
Neural Stem Cells
Epithelial Stem Cells
Skin Stem Cells
Fortier LA. Stem cells: Classifications, controversies, and clinical applications. Vet Surg. 2005;34(5):415–23.

9. Sources of Stem Cells
Mesenchymal
Stem Cells
Adipose
Tissue
Bone Marrow
Umbilical
Cord
Hematogenous
Stem Cells
Cord Blood
Peripheral
Blood
Bone Marrow

10. Mechanism of Action
Stem Cell
Implantation on
the Injured Site
Cell
Differentiation
and Regeneration
Improvement
Inefficient
Differentiation and
Regeneration of
Implanted Cells
Secretion of Paracrine Factors

11. The Paracrine
Effect
 MSCs secret a wide spectrum of
paracrine factors that exert
different functions on its vicinity.
- In the form of vesicles,
cytokines, growth factors, etc
- Microenvironment dependent
(Eg. stress-induced, molecular
stimulated)
- Source-dependent

12. MSC
- Mesenchymal stem cells
(MSCs) are fibroblast-like
multipotent adult stem cells
derived from multiple tissue
(including bone marrow,
adipose tissue, umbilical cord,
and dental pulp) with the
capacity to self-renew.
- MSC characterization was
proposed by the International
Society for Cellular Therapy
(ISCT) to aide in cell culture
consistency
1) be plastic adherent when kept under standard culture conditions
2) express the proper positive and negative MSC markers and
3) retain a multipotent phenotype with the ability to differentiate into adipocytes,
osteoblasts and chondrocytes under the standard differentiation conditions.

13.  One of the main
advantages of MSCs is
their immunomodulatory
properties.
Andrzejewska A, Lukomska B, Janowski M. Concise Review: Mesenchymal Stem Cells: From Roots to Boost.
Vol. 37, Stem Cells. 2019. p. 855–64.

14. Andrzejewska A, Lukomska B, Janowski M. Concise Review: Mesenchymal Stem Cells: From Roots to Boost.
Vol. 37, Stem Cells. 2019. p. 855–64.

15. Andrzejewska A, Lukomska B, Janowski M. Concise Review: Mesenchymal Stem Cells: From Roots to Boost.
Vol. 37, Stem Cells. 2019. p. 855–64.

16. Allogenic MSC: Safety Profile
1) Poor expression of Human Leukocyte Antigen (HLA-II)
2) Undifferentiated & differentiated MSC do not elicit alloreactive lymphocyte
proliferative responses & modulate immune responses.
3) MSC hypoimmunogenic & suppress T cell alloproliferation in mixed lymphocyte
reactions.

17. Allogenic MSC: Safety Profile
1. Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 2000;28:875-84.
2. Le Blanck K et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003; 31(10):890-6
3. Montespan F et al. O Osteodifferentiated Mesenchymal Stem Cells from Bone Marrow and Adipose Tissue Express HLA-G and Display Immunomodulatory Properties in HLA-Mismatched Settings: Implications in Bone Repair Therapy. J of Immun Research
2014:230346
4. Ryan JM et al. Mesenchymal stem cells avoid allogeneic rejection. J Inflamm 2005,2:8
Low Expression of
HLA
- Lack of MHC
- Lack of costimulatory
molecule expression
Disrupts NK cell,
CD8+, and CD4+
functions
- Hypoimmunogenic
- Modulation of immune
function
Production of
Prostaglandin, IL-10,
and expression of IDO
(indolemine 2,3-
dioxygenase)
- Suppressive local
microenvironment

18. Tissue Engineering Triad
SCAFFOLD
SIGNALLING MOLECULES
CELLS
IMPROVEMENT
Time
Appropriate
environment
Hydroxyapatite
Osteogenic cells BMP
Mechanical stability,
infection control
Fracture healing

19. Tissue Engineering
Triad
 1. A scaffold that provides structure
and substrate for tissue growth and
development
 2. A source of cells to facilitate
required tissue formation
 3. Growth factors or biophysical
stimuli to direct the growth and
differentiation of cells within the
scaffold
 However, not only are these
components individually important,
understanding their interactions is
key for successful tissue engineering
Murphy CM, O’Brien FJ, Little DG, Schindeler A. Cell-scaffold interactions in the bone tissue engineering triad. Vol. 26, European Cells and
Materials. 2013. p. 120–32.

20. Components of the Tissue Engineering
Triad
OSTEOGENIC CELLS
Cells with the capability of
differentiating and
regenerating
e.g. osteogenic progenitor
cells
SCAFFOLD
As a site for cell adhesion
and provide protection to
prevent cell damage: a
home for the implanted
cells
e.g. hydroxyapatite,
hyaluronic acid
SIGNALLING
MOLECULES
Substances that give
stimuli for the
differentiation,
development, and
regeneration of cells
e.g. bone morphogenetic
protein (BMP)

21. Principal
cell
therapeuti
c strategies
for treating
diseased or
injured
tissues
 (1) implanting isolated cells
 whole cell populations can be directly transplanted or isolated
cells can be cultured and expanded ex vivo prior to re-
implantation
 (2) implanting a construct assembled from cells and
scaffolds
 deliver a combination of whole cell isolates or ex vivo cultured
cells seeded onto a substrate template
 (3) in situ tissue regeneration by native cells
 In order to modulate the migration and tissue-appropriate
differentiation of endogenous progenitors, drugs capable of
affecting regulatory signals or proteins involved with the
regulatory signalling cascade can be locally delivered
 For example, cells can be engineered to produce VEGF to
stimulate angiogenesis or rhBMP-2 to promote
osteoblastogenesis
Murphy CM, O’Brien FJ, Little DG, Schindeler A. Cell-scaffold interactions in the bone tissue engineering triad. Vol. 26, European Cells and
Materials. 2013. p. 120–32.

22.  1. Pore size, pore interconnectivity, and total
porosity are essential considerations in
scaffold development
 2. Optimal pore size varies depending on
the biomaterials used and application of
the construct
3. Cells travelling through larger pores may
migrate slower, but their directional movement
allow them to travel further into the scaffold.
4. Larger pore size can overcome the
advantages of specific surface area by
increased cell migration and scaffold infiltration
Murphy CM, O’Brien FJ, Little DG, Schindeler A. Cell-scaffold interactions in the bone tissue engineering triad. Vol. 26, European Cells and
Materials. 2013. p. 120–32.

23. UC-MSC for Fracture Non-
Union
• Patients diagnosed with fracture non-
union are treated with UC-MSC based on
the diamond concept / tissue engineering
• Routine follow up for x-ray and functional
asssessment

24. Research
on Stem
Cell:
Statistics

25. Research on MSC

26. Research Topics on MSC

27. Stem Cell:
Potential
Uses

28. Ongoing Stem Cell Research
in RSCM
 Knee osteoarthritis
 Fracture non-union
 Fracture non-union
with bone defect
 Spinal cord injuries
 Tuberculous
spondylitis
Diabetes mellitus
 Glaucoma
 Burn injury
 Erectile dysfunction
 Stroke
 Cerebral palsy

29. MSC for Osteoarthritis
• Intraarticular injection of UC-MSC
for patients with knee osteoarthritis
• UC-MSC given once, followed with
intraarticular injection of
hyaluronic acid
• Routine follow up using
questionnaire, x-ray, and MRI T2
map

30. Comparison with Other Studies
• In this study, we also noted that the greatest improvement of knee function was
observed after 6 months of follow-up. This finding is in line with previous studies,
which found that the maximum results were achieved at 6 months of follow-up but
decline afterwards.
• Centeno, in May 2008, administered MSC in one subject with knee OA and
obtained satisfactory result in the 6th
month.
• A trial by Emadedin in 2012 reported MSC transplantation in 6 patients with knee
OA. The result was satisfactory on the 6th
month, but, slight decline was found on
the 12th
month. However, the patients experienced improvement when compared
to the baseline.

31. UC-MSC for Bone Defect

32. UC-MSC for Spinal Cord
Injuries
 Implantation of UC-MSC in cases of spinal cord injuries
are giving promising results
Muscle mass
improvement
Erectile function
improvement
Improvement on
ejaculation
Improvement on
sensation
Sensory
improvement?
Motoric
improvement?

33. OBSTACLES TO CLINICAL APPLICATIONS
1. Immunorejection by Recipient
 One of the commonly cited advantages of the use of MSCs compared to ES cells is the
use of autogenous cells, and therefore avoidance of immune rejection by the recipient.
 Allogenous MSCs appear to be immunoprivileged and could provide a readily
available source of MSCs, but they would also carry the risks of disease transmission
from donor to recipient
1. Engraftment
 The issue of localization of stem cells to injured tissues becomes important when
considering the application of stem cell therapy to areas or tissues not amenable to
direct injection
 One of the fundamental questions regarding stem cell engraftment is the importance
of the actual number or percentage of donor stem cells in the recipient tissue.

34. Conclusion
• Stem cell treatment yields promising
results in various cases
• We still have a long way to go; research
on stem cell is still developing

35. Thank you