g., chondrogenesis is predominantly a prenatal event in skeletogenesis, while adipogenesis is entirely postnatal [41]. Furthermore, a wealth of evidence, albeit circumstantial in large part, highlights the ability of individual cell types regarded as differentiated to modulate into different phenotypes.

For example, chondrocytes can revert to fibroblasts [42] and [43] or osteoblast-like cells in vitro and in vivo [44] and [45], or even to bone marrow stromal cells in vivo [46]; bone marrow stromal cells can convert into adipocytes in vivo [47]. This “plasticity” of the stromal system (not to be confused with the once claimed, and now luckily AG-014699 cost dispelled, “trans-differentiation” ability of any cell to generate any cell, “turning blood into brain” [48], “brain into blood” [49], “blood into muscle” [50], “muscle into blood” [51], and water into wine [52]) remains to be understood mechanistically, but may be seen as one defining feature of the system and of its unique nature. Nonetheless, the differentiation potential of skeletal stem cells ERK inhibitor solubility dmso is strictly limited to phenotypes that belong to the skeleton: cartilage, bone, fat, fibroblasts and the bone marrow stroma itself are

the only progenies of the marrow stromal stem cells. Skeletal stem cells, like all other kinds of postnatal stem cells, are committed and system-specific, and are not pluripotent. Finally, all cell types in the stromal system exist within an extracellular matrix. This is another noted peculiarity of the stromal system compared to other stem cell-dependent tissues such as blood or epithelial tissues. As the extracellular matrix embodies differentiation cues, maintenance of an individual phenotype within the stromal system is partly regulated “in trans”; constant remodeling of the extracellular matrix makes the “in trans” determination of phenotype inherently unstable. This instability may have been conserved as a specific adaptive function, other than constant and fast

cell replacement such as in blood or epithelial tissues. These adaptive responses include the integrated remodeling of Molecular motor hard tissues with that of soft and fluid tissues. Following the disruption of soft tissue remodeling by ablation of the pivotal protease for collagen degradation, MT1-MMP, vicarious remodeling of bone disrupts skeletal integrity [53]. The adaptive co-regulation of skeletal and hematopoietic physiology involves remodeling of the bone marrow (e.g., timed generation of yellow (adipose) marrow during postnatal growth and aging, and local vascular remodeling) [54]. In a way, one of the notions that come from the existence of skeletal stem cells and the stromal system is that remodeling of bone is part of a much broader adaptive response, which involves the coordinated remodeling of other connective tissues.