Generation of mesenchymal stem cells from human induced pluripotent stem cells (iPS) for the treatment of limb ishcemia

Dr Lian, Qizhou   (Principal Investigator (PI))

Professor Tse Hung Fat   (Co-Investigator)

12

2010-01-01

60000

Generation of mesenchymal stem cells from human induced pluripotent stem cells (iPS) for the treatment of limb ishcemia

cardiac infarction, induced pluripotent stem cells, mesenchymal stem cells, transplantation

Cell Biology,Cardiovascular Research

200907176179

Small Project Funding

2009

Completed

Human mesenchymal stem cells (MSCs), also named multipotent stromal cells have emerged as a promising cell type in regenerative medicine, including in the treatment of myocardial and limb ischemia(Kim et al., 2006; Minguell and Erices, 2006; Pittenger and Martin, 2004). In the majority of pre-clinical and clinical studies, MSCs are derived from bone marrow (BM). However, there are several potential shortcomings in using BM derived-MSCs (BM-MSCs). BM-MSCs have a limited capacity of proliferation, quickly loss of differentiation potential and production of protective factors during ex-vivo expansion before possible therapeutic use (Crisostomo et al., 2006; Kretlow et al., 2008; Wagner W, 2009 ). Importantly, it has been shown that aging and aging-related disorders significantly impair the survival and differentiation potential of BM-MSCs, and thus limit their therapeutic efficacy (Heeschen et al., 2004; Jiang et al., 2008; Roobrouck et al., 2008; Xin et al., 2009). As a result, there is an emerging interest in the identification of alternative cell sources for MSCs. Recent breakthrough in the generation of induced pluripotent stem cells (iPSCs) from adult somatic cells by reprogramming techniques (Takahashi et al., 2007; Yu et al., 2007) provides a possibility to generate high yield of patient-specific MSCs. However, the differentiation potential of human iPSC into functional MSC and their therapeutic efficacy have never been demonstrated. This study was aimed to generate and characterize human iPSCs-derived MSC and to investigate its biological functions for the treatment of limb ischemia. Our specific objectives are summarized as following: Objective 1: To generate MSCs from human iPSC (iPSC-MSC ) Objective 2: To study basic biology and multipotency of iPSC-MSC. Objective 3: To transplant iPSC-MSC into mice with severe limb ischemia to determine protective effects of iPSC-MSC . Reference Crisostomo, P.R., Wang, M.J., Wairiuko, G.M., Morrell, E.D., Terrell, A.M., Seshadri, P., Nam, U.H., and Meldrum, D.R. (2006). High passage number of stem cells adversely affects stem cell activation and myocardial protection. Shock 26, 575-580. Heeschen, C., Lehmann, R., Honold, J., Assmus, B., Aicher, A., Walter, D.H., Martin, H., Zeiher, A.M., and Dimmeler, S. (2004). Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation 109, 1615-1622. Jiang, S., Kh Haider, H., Ahmed, R.P., Idris, N.M., Salim, A., and Ashraf, M. (2008). Transcriptional profiling of young and old mesenchymal stem cells in response to oxygen deprivation and reparability of the infarcted myocardium. J Mol Cell Cardiol 44, 582-596. Kim, S.W., Han, H., Chae, G.T., Lee, S.H., Bo, S., Yoon, J.H., Lee, Y.S., Lee, K.S., Park, H.K., and Kang, K.S. (2006). Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger's disease and ischemic limb disease animal model. Stem Cells 24, 1620-1626. Kretlow, J.D., Jin, Y.Q., Liu, W., Zhang, W.J., Hong, T.H., Zhou, G., Baggett, L.S., Mikos, A.G., and Cao, Y. (2008). Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells. BMC Cell Biol 9, 60. Minguell, J.J., and Erices, A. (2006). Mesenchymal stem cells and the treatment of cardiac disease. Exp Biol Med (Maywood) 231, 39-49. Pittenger, M.F., and Martin, B.J. (2004). Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 95, 9-20. Roobrouck, V.D., Ulloa-Montoya, F., and Verfaillie, C.M. (2008). Self-renewal and differentiation capacity of young and aged stem cells. Exp Cell Res 314, 1937-1944. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872. Wagner W, B.S., Horn P, Krunic D, Walenda T, Diehlmann A, Benes V, Blake J, Huber FX, Eckstein V, Boukamp P, Ho AD. (2009 ). Aging and replicative senescence have related effects on human stem and progenitor cells. PLoS One Jun 9;4(6):e5846. Xin, Y., Wang, Y.M., Zhang, H., Li, J., Wang, W., Wei, Y.J., and Hu, S.S. (2009). Aging Adversely Impacts Biological Properties of Human Bone Marrow-derived Mesenchymal Stem Cells: Implications for Tissue Engineering Heart Valve Construction. Artif Organs. Yu, J.Y., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.