What is the MSC Niche?
Mesenchymal Stem Cells (MSCs) are a heterogeneous population of cells which are primarily found in the bone marrow (and fat pads) and are recruited at site of injury and are known to participate in the healing and repair of almost all tissues within the human anatomy. In spite of decades of research highlighting the importance of MSCs our understanding of what constitutes a MSC niche is very limited and the factors that influence the heterogeneity of the MSC population is not well understood. There is mounting evidence that hematopoietic stem cells (HSCs) and marrow-derived stem cells (MSCs) might share a same progenitor. Pioneering work by Darwin Prockop and Edwin Horwitz have shown through grafting studies in irradiated mice, that there exists a sub-population of cells in the bone marrow, that perhaps require a bone environment for self renewal, i.e., the bone matrix might be the niche, and this population of cells can give rise to both HSCs and osteoblasts. Our own efforts on are focused on understanding the role of "heterogeneity" in MSC pluripotency and developing systems that can mimic the natural niche of MSC and in doing so develop synthetic platform for MSC self-renewal and transplantation.
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Our ongoing efforts in understanding the factors that influence MSC fate has unraveled a crucial role for mechanobiology and bio-physicochemcial properties of bone mineral phase in dictating MSC differentiation and pathway choice in bone formation. Using a biomimetic hydroxyapatite developed in our lab we have unraveled a hitherto unknown role for bone mineral phase in dictating bone formation. Bone formation can occur either via the deposition of osteoblasts differentiated from MSCs (intramembranous ossification (MO)) or via the remodeling of a cartilage template deposited by MSC condensate (endochondral ossification (EO)). We have discovered that in presence of bone-like mineral phase bone formation by MSCs exclusively occurs only via IMO even in presence of soluble signals that promote EO. Furthermore, we have discovered that bone-like mineral induces hyperstimulation of calcium sensing receptor (CaSR) in MSCs and a down-regulation of parathyroid hormone 1 receptor (PTH1R) resulting in inhibition of chondorogensis and as a consequence bone formation via the EO pathway.