Role of pluripotent stem cells (PSCs) isolated from adult tissue in bone tissue regeneration

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While minor bone injuries heal and/or regenerate on their own, major defects caused by congenital anomalies, trauma and surgical excision of diseased tissues, overwhelm bones regenerative capacity, resulting in multiple and costly interventions, and prolonged patient suffering. Current treatments have met with varying degrees of success, however are associated with several drawbacks. Tissue engineering (TE) techniques, that use different combinations of, scaffolds, growth factors, and osteoprogenitor cells, applied directly into the bone defect; hold great promise for achieving optimal healing, while eliminating many of the drawbacks. Using these techniques we and others have purified and expanded MSC, EPC and BM-MNC, and in different combinations have seeded them onto scaffolds and, in animal models, treated large bone defects, and have demonstrated improved bone healing.While most combinations of purified cells promote healing, we were surprised to find that the rate and quality of healing was not significantly better than, conventional treatment with autologous bone grafts. These unexpected findings led us to reexamine the constituents of autologous grafts, in the BM-MNC fraction, in an attempt to identify which is/are the primary actor(s) promoting the observed enhanced bone healing. The BM-MNC used in these treatments consists of a heterogeneous mix of mononuclear cells containing mesenchymal stem cells, hematopoietic progenitor cells, endothelial progenitor cells, and pluripotent stem cells. The latter have been described by several groups, and depending on the isolation protocol used, have been assigned different names; spore-like stem cells, multipotent adult stem cells (MASCs), multilineage-differentiating stress enduring (Muse) cells, multipotent adult progenitor cells (MAPs), very small embryonic-like stem cells (VSEL). They have been found in most adult tissues, have been shown to be pluripotent in an in vivo models and have been shown to stimulate new bone formation.Based on the above we formed a hypothesis that VSEL cells, within BM-MNC, play a key role in the regenerative response in bone following injury. To test this hypothesis, we will measure and compare the effects of BM-MNC, with and without VSEL cells, and VSEL cells alone, on bone healing in a rat femur critical size bone defect model. We will structure the experiments in order to answer the following questions: Are VSEL cells, or their descendants, present in healing bone in the rat femur? If so do VSEL cells contribute to the pro-healing response observed in BM-MNC based treatments? And what aspect of bone healing do VSEL cells contribute to?