2012 AAA Keynote and Plenary Speakers

During development, cartilage- and bone-forming stem cells collaborate with vascular, nerve and hematopoietic cells to produce skeletal elements and the joints that link them together. When activated during postnatal repair, stem cells in the periosteal regions or recruited from bone marrow via the circulation are fully capable of healing most fractures. However, regeneration of skeletal tissues fails in patients with loss of articular cartilage (osteoarthritis), large, localized defects in bone (when large tumors or necrotic bones are removed) or generalized bone loss (osteoporosis). Bone marrow-derived mesenchymal stem cells, long thought of as promising for cartilage, bone and skeletal muscle repair/regeneration, appear to be more important for the growth factors they produce than for their in vivo ability to differentiate into specific cell lineages. This talk will discuss the discovery that differentiated vascular endothelial cells can undergo a conversion into mesenchymal stem-like cells (endothelial-mesenchymal transition; EndMT); these stem-like cells can in turn differentiate into chondrocytes, osteoblasts or adipocytes in vitro and in vivo. Thus, blood vessels may not only bring blood supply and oxygen to tissues undergoing repair but may also provide mesenchymal stem cells for cell differentiation. EndMT is regulated via TGF/BMP receptor signaling. In patients with Fibrodysplasia ossificans progressiva (FOP), where skeletal muscle and associated soft tissues progressively turn into bone, endothelial cells contribute significantly to the chondrocytic and osteoblastic cells that form the ectopic bone. FOP patients are heterozygous for activating mutations in the BMP type I receptor ALK2. However, EndMT can also be induced in endothelial cells from individuals without FOP when BMP receptor signaling is activated in the absence of inhibitors of EndMT. One of these inhibitors, Vascular Endothelial Growth Factor-A (VEGF), is critical at skeletal tissue repair sites by stimulating angiogenesis and osteoblast differentiation. New insights into mechanisms by which VEGF regulates stem cell differentiation suggest that it may be possible to block the negative effect of VEGF on EndMT without affecting its positive effect on osteoblast differentiation.