Abstract
To guide the use of human mesenchymal stem cells (MSCs) toward clinical applications, identifying pluripotent-like-markers for selecting MSCs that retain potent self-renewal-ability should be addressed. Here, an insulin-like growth factor 1 receptor (IGF1R)–expressing sub-population in human dental pulp MSCs (hDSCs), displayed multipotent properties. IGF1R expression could be maintained in hDSCs when they were cultured in 2% human cord blood serum (hUCS) in contrast to that in 10% fetal calf serum (FCS). Cytokine array showed that hUCS contained higher amount of several growth factors compared to FCS, including IGF-1 and platelet-derived growth factor (PDGF-BB). These cytokines modulates the signaling events in the hDSCs and potentially enhances engraftment upon transplantation. Specifically, a bidirectional cross-talk between IGF1R/IGF1 and CXCR4/SDF-1α signaling pathways in hDSCs, as revealed by interaction of the two receptors and synergistic activation of both signaling pathways. In rat stroke model, animals receiving IGF1R+ hDSCs transplantation, interaction between IGF1R and CXCR4 was demonstrated to promote neuroplasticity, therefore improving neurological function through increasing glucose metabolic activity, enhancing angiogenesis and anti-inflammatiory effects. Therefore, PDGF in hUCS-culture system contributed to the maintenance of the expression of IGF1R in hDSCs. Furthermore, implantation of IGF1R+ hDSCs exerted enhanced neuroplasticity via integrating inputs from both CXCR4 and IGF1R signaling pathways.
Highlights
Neuronal SDF-1αand its receptor CXCR4 co-expressing in the adult cerebral cortex and hippocampus suggest that they may exert neuromodulatory actions in these regions
In order to eschew the animal product and prion contamination in the in vitro stem cell culture system, we developed a unique culturing cocktail using low percentage of human umbilical cord serum to expand the human dental pulp stem cells. hUCS is endowed with a rich source of different cytokines and has been applied to culture cord blood HSCs22, T cells[23] and BM MSCs24
To further quantitate the concentration of specific cytokines, ELISA of platelet-derived growth factor (PDGF)-BB and insulin-like growth factor 1 (IGF1) were performed in the hUCS and fetal calf serum (FCS)
Summary
Neuronal SDF-1αand its receptor CXCR4 co-expressing in the adult cerebral cortex and hippocampus suggest that they may exert neuromodulatory actions in these regions. Development of neural cell lineages is highly dependent on the IGF1/IGF1R signaling pathway[17]. Whether these two signaling cascade could interact to modulate the cellular physiology. Investigation on interactions between different receptor classes is essential for understanding the mechanisms through which cells process multiple signaling inputs simultaneously, yet the potential cross-talk and interaction between IGF1R and CXCR4 signaling pathways on stem cells proliferation and self-renewal has not been explored. We speculated that receptors crosstalk between IGF1R and CXCR4 demonstrated in the metastatic MDA-MB-231 cells[25] might synergistically stimulate growth signaling in the IGF1R+ hDSCs. We hypothesized that cross-talk between IGF1R and CXCR4 signaling pathways in IGF1R+ hDSC might exert autocrine/paracrine induction of an additive survival signal to enhance neurite regeneration and neuroplasticity in hDSC-transplanted stroke model
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