1. Shen Bin 9-20-2015 Journal Club

2. What is MSCs?  Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into a variety of cell types [1] including: osteoblasts (bone cells) [2] chondrocytes (cartilage cells) [3] myocytes (muscle cells)[4] and adipocytes (fat cells). 1.Nardi, N. Beyer et al. Stem Cells. 2006 2.Oni OO et al. J Bone Joint Surg Am. 1992 3.Brighton CT et al. J Orthop Trauma. 1997 4.Pittenger et al. Science. 1999

3. CHARACTERISTICS  Morphology Fibroblast-like  Detection Express :CD73, CD90 and CD105 Lacking the expression: CD11b, CD14, CD19, CD34, CD45, CD79a and HLA-DR  Self-renewal and differentiation capacity Great capacity for self-renewal osteoblasts, adipocytes, and chondrocytes, myocytes neurons, hepatocyte and beta-like cells.  Immunomodulatory effects avoid allorecognition ○ interfere with dendritic cell and T-cell function ○ secreting cytokines Jiang Y et al. Nature, 2002 Franco Lambert AP et al. Differentiation. 2009 Engler AJ et al. Cell. 2006 Ryan JM et al. Journal of Inflammation. 2005 Ryan JM et al. Clinical & Experimental Immunology. 2007 Phinney DG et al. Stem Cells. 2007

4. MEDICAL USE  Intravenous transplantation systemic diseases like graft versus host disease and sepsis  Increase the local concentration of cells inflammatory bowel disease  Direct injection or placement of cells into a site in need of repair orthopedic applications chondral defects …… Heirani-Tabasi A et al. Journal of Genes and Cells. 2015 Manieri NA et al. Current Opinion in Gastroenterology. 2011 Fischer UM et al. Stem Cells and Development. 2009 Wakitani S et al. Journal of Tissue Engineering and Regenerative Medicine. 2007

5. IMMUNOMODULATION MSCs effect proliferation, maturation and cytokine secretion by different immune cells. NK cells, Natural Killer Cells; iDCs, Immature Dendritic Cells; APCs, Antigen Presenting Cells.

6. CELL AND ORGAN TRANSPLANTATION

9. Graft vs. Host Disease  HSC transplantation GVHD Corticosteroids  MSCs from the donor and controls inhibited patient lymphocyte proliferation by 90% before and after transplantation

10. REGENERATIVE MEDICINES  Transdifferentiation of MSCs to β cells Small molecular chemicals, growth factors Genetic modifications, pdx1  Hepatocytes  cardiac tissues cardiac myocytes  Ectodermal differentiation neurons, and astrocytes

11. GENE CARRIERS  Genetic modifications of MSCs have been performed to improve the MSC efficacy in tissue repair/regeneration  Secretion of growth factors neurotropic factors Liver tp, HGF, BDNF, IGF-1 and VEGF cytoprotective effects and lead to tissue repair

12. CHALLENGES TO MSC-BASED THERAPY  poor delivery of MSCs  spontaneous malignant transformation of MSCs  unwanted differentiation MSC differentiation to myofibroblasts instead of hepatocytes is unwanted and leads to worsening of liver injury

13. CLINICAL TRIALS