Furthermore we found that downregulation of endogeneous BMP

Furthermore, we found that downregulation of endogeneous BMP2 suppressed osteogenesis and increased adipogenesis, similar to the effect of miR-17-5p or miR-106a overexpression. Moreover, inhibitory effects of miR-17-5p and miR-106a on osteogenesis and adipogenesis of hADSCs could be reversed by BMP2 RNA interference. These results further indicated that miR-17-5p and miR-106a promote adipocyte differentiation and suppress osteogenesis directly by negatively regulating BMP2. MSX2, TAZ, and ID1 have been identified as candidate genes regulated by BMP2 and are involved in the switch between adipocyte and osteoblast differentiation. We found that miR-17-5p overexpression was accompanied by decreased expression levels of TAZ and MSX2, while ID1 showed no change, whereas miR-17-5p inhibitor increased the expression of those proteins, which was consistent with the effects of siRNA for BMP2. Those results confirmed that miR-17-5p and miR-106a mediated the commitment of hADSCs between adipogenesis and osteogenesis directly through targeting BMP2 and then participating in MSX2/TAZ regulated Runx2 and PPARγ pathway. Our studies elucidate the mechanisms underlying selective induction of a tissue specific phenotype by miR-17-5p and miR-106a. Thus these findings could improve hADSCs-based cell therapy for osteogenesis- and adipogenesis- related disorders.
Conflict of interest
Acknowledgments This study was supported by grants from the ‘863 Projects’ of Ministry of Science and Technology of P.R. China (No. 2011AA020100), National Natural Science Foundation of China (No. 30830052), the National Key Scientific Program of China (No. 2011CB964901), and Program for Cheung Kong Scholars and Innovative Research Team in University-PCSIRT (No. IRT0909).
Introduction Neurodegenerative disorders and trauma of the central nervous system (CNS) result in loss of neural ruthenium red and include inflammatory and immune processes. Efforts have been made at finding effective treatments to rescue neural cells and counteract secondary degeneration and inflammation. Pharmacological therapy may slow down degenerative processes but are still limited when it comes to restoration of CNS functions. Human neural stem/progenitor cells (hNPCs) can be derived from pluripotent embryonic stem cells (hESCs), fetal CNS or induced pluripotent stem cells (iPSCs) and have shown potential to restore functions. Improvements of motor function have been demonstrated in numerous animal models of Parkinson\'s disease (Morizane et al., 2008) and spinal cord injury (SCI) (Tetzlaff et al., 2011; Fujimoto et al., 2012). A rejection of donor neural cells is however an inevitable concern, which must be addressed for any such therapy. The presence of human leukocyte antigen (HLA) class I and II molecules (Odeberg et al., 2005; Ubiali et al., 2007; Johansson et al., 2008; Laguna Goya et al., 2011) in conjunction with co-stimulatory molecules CD40, CD80 and CD86 (Odeberg et al., 2005) on hNPCs implies a risk for recognition and rejection by non-compatible alloreactive immune cells after transplantation. Varying results have been reported in studies analyzing allogeneic T-cell proliferation stimulated by hNPCs and their derivates from different origins in in vitro assay. We previously reported that hNPCs derived from first trimester nervous system (hfNPCs) did not trigger an allogeneic lymphocyte response (Odeberg et al., 2005). Similar findings on oligodendrocytes derived from hESCs were reported by Okamura et al. (2007). In contrast, Preynat-Seauve et al. (2009) found that hESC-derived NPCs (hESC-NPCs) elicited a significant T cell proliferation. Today, we also experimentally have the option to derive human neural cells from iPSCs (Takahashi and Yamanaka, 2006; Karumbayaram et al., 2009) or by direct induction of differentiated cells to neural cells (Vierbuchen et al., 2010), which may offer autologous neural cell therapy with reduced ethical concerns and less risk of rejection. However, even transplantation of syngeneic iPSCs can cause an immune response (Zhao et al., 2011). Irrespective of their origin, in vitro modified and expanded donor cells may present changes in cellular characteristic and protein expression, putting them at risk of being rejected. The aim is to reduce the rejection risk with preserved therapeutic potential.