"Mesenchymal" stem cells in human bone marrow (skeletal stem cells): a critical discussion of their nature, identity, and significance in incurable skeletal disease.

At the turn of a decade of intensive wishful thinking, "mesenchymal stem cells" are changing their profile, while retaining their charm. As hopes to turn bone into brain or vice versa seem on the wane, we learn (1) that the archetypal "mesenchymal stem cell," the skeletal stem cell found in the bone marrow, can be directly identified as a specialized type of mural cell/pericyte, found in the wall of sinusoids and long known as adventitial reticular cells; (2) that bone marrow skeletal stem cells are also defined by expression of CD146, and can self-renew in vivo, while giving rise to skeletal tissues, and therefore earn consideration as bona fide stem cells; (3) that a broader class of microvascular mural cells endowed with clonogenicity and progenitor properties may exist in other tissues, although their true potency needs to be firmly established by stringent assays and thorough comparisons across tissues; (4) that bone marrow skeletal stem cells display unique angiopoietic and hematopoietic niche-related functions, consisting in their ability to transfer the hematopoietic microenvironment and to guide the assembly of microvascular networks, which seem to define their inherent biology; and (5) that use of skeletal stem cells as disease models, and as models of high-risk strategies for cell and gene therapy specifically in incurable skeletal diseases, may provide new challenges for the next decade, and perhaps reward for medicine in the one that follows.