Mesenchymal Stem Cells: a new trend for cell therapy Animal Molecular Physiology Lab Ran Kim

Index Ⅰ. Mesenchymal Stem Cells Ⅱ. Therapeutic mechanisms of MSCs Ⅲ. MSCs for tumor therapy Ⅳ. Unsolved problem and challenges Ⅴ. Summary

Stem Cells • unspecialized cells with the ability to renew themselves • differentiate into various specialized cells types

Stem Cells ESCs ASCs iPSCs type origin blastocyst of embryo many tissues reprogramming of somatic cells strength pluripotent (3 germ layers) self-renewal and high replicative capacity autologous clinical safety and efficacy data typically lineage committed totipotent (3 germ layers and trophoblast) large reservoir of cells weakness immunological concerns subject to ethical debate potential for teratoma and teratocarcinoma currently no clinical trial data limited number limited replicative capacity lineage restricted no clinical data

Ⅰ. Mesenchymal Stem Cells markers (+) CD13, CD29, CD49e, CD54, CD90 (-) CD14, CD31, CD34, CD45, CD49d, CD106

Ⅰ. Mesenchymal Stem Cells Acta Pharmacol Sin. 2013;34(6):747–754.

Ⅱ. Therapeutic mechanisms of MSCs 1. Homing efficiency The life and fate of mesenchymal stem cells Cytokine/receptor pair SDF-1/CXCR4, SCF/c-Kit, HGF/c-Met, VEGF/VEGFR, PDGF/PDGFR, MCP-1/CCR2, HMGB1/RAGE Front. Immunol. 2014;5:148.

Ⅱ. Therapeutic mechanisms of MSCs Front. Immunol. 2014;5:148.

Ⅱ. Therapeutic mechanisms of MSCs Mol Ther. 2008;16(3):571-579.

Ⅱ. Therapeutic mechanisms of MSCs 2. Differentiation potential and tissue engineering

Ⅱ. Therapeutic mechanisms of MSCs 3. Product of trophic factors J Cell Biochem. 2006;98(5):1076-1084.

Ⅱ. Therapeutic mechanisms of MSCs 4. immunomodulation Immunomodulatory properties of mesenchymal stromal cells Blood. 2007;110(10):3499-3506.

Ⅲ. MSCs for tumor therapy 1. MSC delivery of interleukins Blood 2013;122:e23-e32

Ⅲ. MSCs for tumor therapy Cytokine Gene-engineered MSCs • AdIL-12-engineered MSCs significantly suppressed tumor growth and enhanced weight loss • AdIL-12-MSC therapy resulted in significant increment of apoptotic index versus controls. A tumor-selective biotherapy with prolonged impact on established metastases based on cytokine gene-engineered MSCs. Mol Ther. 2008;16(4):749-756.

Ⅱ. MSCs for tumor therapy 2. Interferons INF-β: anti-proliferative and proapoptotic effect  Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors Cancer Res. 2002;62(13):3603-3608.

Ⅲ. MSCs for tumor therapy 3. Prodrug a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug Mol Ther. 2010;18(1):223-231.

Ⅲ. MSCs for tumor therapy 4. oncolytic viruses 5. antiangiogenic agents 6. Pro-apoptotic proteins Viruses. 2015;7(12):6200-6217.

Ⅳ. Unsolved problem and challenges • interactions between MSCs and the inflammatory milieu in which they reside and the therapeutic mechanisms of MSCs • which source should be used for which disease, which route of administration is best suited for a particular disease • the parameters for monitoring clinical effectiveness • established standards for cell expansion protocols, product quality, and safety controls • establish regulatory polices to meet the challenges of this newly emerging and rapidly advancing field and benefit patients suffering a wide array of diseases.

Ⅴ. Summary Acta Pharmacol Sin.2013;34(6):747–754.