28 May 2022

Stem Cell Science : Mesenchymal Stem Cells and Clinical Applications

Hadyanto Lim
Department of Pharmacology and Pharmacy,
Biomedical Sciences Program, Postgraduate Study,
Universitas Methodist Indonesia
Goals

∎ Stem cell biology.

∎ Sources and mechanisms of mesenchymal stem cells (MSCs).
∎ Detection of stem cells in culture and peripheral blood.
∎ Regulation of differentiation of MSCs.
∎ Applications of MSCs in treating diseases.
 What Are Stem Cells ?

∎ Stem cells reproduce themselves (self-renewal).

∎ Stem cells generate progeny destined to differentiate into functional cell types.
∎ Stem cells persist for a long time.
∎ Stem cell behavior is regulated by the microenvironment (niche).
The Science of Stem Cells
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Figure 1.1 A consensus diagram showing stem cell behavior. (Modified from Slaclc J'M'W' (2013)' Essential
Slack MW. The science of stem cells. Wiley Blackwell 2018.
Developmental Biology, 3rd edn. Reproduced with the permission of John Wiley and Sons')
Morrison SJ, Kimble J. Nature 2006; 441: 1068-74.
Hadyanto Lim.Stem Cell Kardiovaskuler ed. 2, PT Sofmedia, 2012, Jakarta, p. 46
pluripotent stem cells (iPSC)' There are vari-
 Dynamic microenvironment of stem cell niche

Stem cell behavior : the stem cells continue to divide so long as they are in contact with the niche,
and they differentiate when they are no longer in contact.

Slack MW. The science of stem cells. Wiley Blackwell 2018; Spradling A et al. Nature 2001; 414: 98-104.
Hadyanto Lim. Stem Cell Kardiovaskuler ed 2 vol 1, PT Sofmedia, 2012, p 100
Adult stem cell Embryonic stem cell Induced pluripotent stem cell

Somatic cells

Oct 4 Klf 4
Embryonic SOX 2 c-Myc (OSKM)
body
Embryonic-like cells
HSC – MSC ESC

Teratoma

Regeneration
 Salamander Regeneration was completed 12 weeks after injury at 9 years old

Kumar A et al. Science 2007;318:772-7.

Hadyanto Lim. Ilmu Stem Cell : Terapan dalam
Klinis. Penerbit UMI, 2019 Rosenthal LJ et al. Pediatrics 1979; 64:1-3
 Minimal Criteria of MSCs (International Society for Cellular Therapy (ISCT)

(1) Adherence to plastic in standard culture conditions

(2) Expression of the surface molecules CD73, CD90, and CD105 in the absence of CD34, CD45, HLA-DR, CD14
or CD11b, CD79a, or CD19 surface molecules
(3) A capacity for differentiation into osteoblasts, adipocytes, and chondroblasts in vitro

Dominici M, et al. Cytotherapy. 2006; 8:315–17.

 Sources of Mesenchymal Stem Cells (MSCs)

• MSCs can be isolated from different adult tissues preferably :

-bone marrow (BM)
-peripheral blood (PB)
• Adipose tissues (AT) (such as abdominal fat, infrapatellar fat pad, and
buccal fat pad)
• Neonatal birth-associated tissues, including placenta (PL), umbilical cord
(UC), Wharton jelly (WJ), amniotic fluid (AF), and cord blood (CB), and
then stored for future possible applications.

Golchin A et al. Stem Cell Reviews and Reports https://doi.org/10.1007/s12015-020-09973-w

How to detect stem cell markers in the peripheral blood ?

∎ Hematopoietic stem cells : CD34+

∎ Mesenchymal stem cells : CD73+/CD105+, CD90+/CD105+,CD73+/CD90+

Stem Cells In Apheresis Product Collected into the Bag and Administered to Patient
Detection of Stem Cells Marker CD34+ in Mobilized Peripheral Blood Transplantation
Before After
Detection Of Mesenchymal Stem Cells In Mobilized Autologous Peripheral Blood Transplantation
From Patients With Ischemic Heart Disease

Lim H, et al. Virtual Presentation at the Basic Cardiovascular Science (BCVS) 2021, August 25, 2021
Regulation of differentiation of mesenchymal stem cells (MSCs) and their functions
Functions :
∎ Mesenchymal stem cells can differentiate into mesoderm and nonmesoderm-derived tissues.
∎ Immunomodulatory effects.
∎ Key role in maintaining and replenishing endogenous stem cell niches.

Karantalis Y, Hare JM. Circ Res 2015; 116: 1413-1430.

Pittenger MF, et al. Circ Res. 2004;95:9-20
Lim H. Stem cell Kardiovaskuler, PT Sofmedia 2015, p. 174-192
Immunomodulatory effects of MSCs

∎ MSCs suppress proliferation of both T

helper (TH) and cytotoxic T cells (Tc).

∎ Trigger differentiation to TH2 and

regulatory T-cells (Treg), resulting in an anti-
inflammatory environment.

∎ Induce monocytes to M2, an anti-

inflammatory effect.

∎ Suppress B cell proliferation, decreasing the

production of antibodies.

Karantalis Y, Hare JM. Circ Res 2015; 116: 1413-1430.

Exogenous administration of MSCs (green line) inducing endogenous cardiopoietic stem cells
(CSCs; orange line) during cardiac repair after myocardial infarction (MI).

Karantalis Y, Hare JM. Circ Res 2015; 116: 1413-1430.

 What are the mechanism of actions of MSCs ?
Mesenchymal stem cells also contain extracellular vesicles (EV)

• Exosomes : diameter 40-150 nm

• Microvesicles : diameter 150-1000 nm

• Apoptotic bodies : diameter 50-2000 nm

Yin K et al. Biomar Res 2019; 7:8 Sahoo S et al. Circ Res. 2014;114:333-344.
Stem cells secrete extracellular vesicles (EVs) carrying non-coding RNAs (ncRNAs)

Fatima F, et al. Front. Genet. 2017; 8:161.

Mechanisms of action of mesenchymal stem cells (MSCs)

Karantalis Y, Hare JM. Circ Res 2015; 116: 1413-1430.

What are the clinical applications of MSCs

Rodrıguez-Fuentes DE et al. Arch Med Res 2021; 52: 93-101.

Table 1. Distribution of clinical trials on MSCs registered at clinicaltrial.gov by the medical field
Medical # of CT % Phase1 Phase2 Phase3 Phase4 Total
speciality
Traumatology 234 25.9 72 137 23 2 234
Pneumology 99 11.0 43 53 3 0 99
Neurology 97 10.7 31 61 4 1 97
Cardiology 83 9.2 21 50 12 0 83
Immunology 78 8.6 14 50 14 0 78
Hepatology 53 5.9 11 39 2 1 53
Endocrinology 47 5.2 13 30 4 0 47
Dermatology 31 3.4 9 22 0 0 31
Gastroenterology 30 3.3 9 20 1 0 30
Nephrology 27 3.0 12 15 0 0 27
Hematology 25 2.8 9 13 2 1 25
Oncology 24 2.7 10 13 1 0 24
Gynecology 16 1.8 5 11 0 0 16
Psychiatry 16 1.8 2 13 0 1 16
Urology 16 1.8 9 6 1 0 16
Ophthalmology 11 1.2 3 7 1 0 11
Odontology 10 1.1 2 8 0 0 10
Other 6 0.7 3 3 0 0 6
Total 903 100 278 551 68 6 903
Left ventricular (LV) remodeling and potential targets for stem cell therapy

Monisha N. Banerjee MN et al. Circulation Research 2018; 123 : 266-287.

Bone marrow–derived mesenchymal stem cells (MSCs) in clinical trials (POSEIDON, TAC-HFT, PROMETHEUS).

Karantalis Y, Hare JM. Circ Res 2015; 116: 1413-1430

 How MSCs therapy improve lung function ?

⦁ Intravenously MSCs reach the lung within 30

minutes (homing to repair the injured tissues)

⦁ Releases trophic factors including extracellular

vesicles that results in immunomodulation and
a reduction in important inflammatory
mediators.

Armitage J, et al. Eur. Respir. J.; 2018. Li X et al. Ontarget 2017; 8 : 102600–102616.
 Osteoarthritis Mesenchymal stem cell applications in the treatment of osteoarthritis

Felson DT. N Engl J Med 2006; 354:841-848 Zhu C et al. Am J Transl Res 2021;13(2):448-461
Grade 0-1 Grade 2-3 Grade 4 (Kellgren Lawrence)

Diekman BO et al. Curr Opin Rheumatol. 2013;25: 119–126.

Pain improvement resulting from MSC treatment
Cartilage quality improvement from MSC treatment

Orozco L et al. Transplantation 2013;95:1535e1541.

Conclusions

• Stem cells are capable of renewing themselves and differentiation into

different kinds of tissues.

• Mesenchymal stem cells have the immunomodulatory and anti-

inflammatory effects, and can be isolated in culture and peripheral blood.

• Clinical trials have shown the beneficial effects of MSCs in a variety of

diseases such as heart and lung diseases, and osteoarthritis.
Thank you