In early 1970’s, Friedenstein and colleagues were the first to report the presence of fibroblastoid cells that could be flushed out from the adult bone marrow, form colonies on plastic and, when transplanted subcutaneously with appropriate carriers, could make bone and reconstitute a hematopoietic microenvironment. Friedenstein provided the first evidence of the existence in the bone marrow of what later would be called a “mesenchymal stem cell” or MSC. Over the years, it has become progressively clear that such cells, which can differentiate in vitro into a variety of mesenchymal lineages such as osteoblasts, chondrocytes and adipocytes, are not an exclusive feature of the bone marrow, but can also be isolated from other organs and tissues. A large number of studies have provided evidence in support of their plasticity, their potential use for tissue engineering purposes, their extraordinary immunomodulatory properties, as well as their ability to be recruited to sites of injury where they might contribute a “natural in vivo system for tissue repair”. Other studies have attempted the characterization of their cell-surface specific antigens and of their anatomical locations in vivo. However, despite this impressive body of investigations, numerous questions related to the developmental origin of these cells, their proposed pluripotency, and their participation to the physiological processes of bone modeling and remodeling and tissue repair in vivo, are still largely unanswered. Moreover, both a systematic phenotypic in vivo characterization of the MSC population and the development of a reproducible and faithful in vivo model that would test the ability of MSCs to self-renew, proliferate and differentiate in vivo are still just beginning. Lastly, a detailed analysis of the complex network of signaling pathways that very likely regulates their proliferative and differentiation potential has also just begun.

This brief review summarizes the current knowledge and the outstanding questions in the field of the study of mesenchymal stem cells.