Celulas madres

Cell Stem Cell

Commentary
Mesenchymal Stem Cells: Revisiting History, Concepts, and Assays
Paolo Bianco,1,2,5,* Pamela Gehron Robey,3,5 and Paul J. Simmons4,5
of Experimental Medicine and Pathology, La Sapienza University, 00161 Rome, Italy Science Park San Raffaele, 00128 Rome, Italy 3Craniofacial and Skeletal Diseases Branch, Department of Health and Human Services, National Institute ofDental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA 4Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA 5These authors contributed equally to this work. *Correspondence: paolo.bianco@uniroma1.it DOI 10.1016/j.stem.2008.03.002
2Biomedical 1Department

The concept of mesenchymal stemcells has gained wide popularity. Despite the rapid growth of the field, uncertainties remain with respect to the defining characteristics of these cells, including their potency and self-renewal. These uncertainties are reflected in a growing tendency to question the very use of the term. This commentary revisits the experimental origin of the concept of the population(s) referred to as mesenchymalstem cells and the experimental framework required to assess their stemness and function.
The concept of stem cells originated at the end of the 19th century as a theoretical postulate to account for the ability of certain tissues (blood, skin, etc.) to self-renew for the lifetime of an organism even though they are comprised of short-lived cells. Many years later, identification of stem cells asdiscrete cellular entities followed from the development of methods for prospective isolation of stem cell candidates, in parallel with the design of rigorous bioassays to test their potency after transplantation in vivo. The currently popular concept of mesenchymal stem cells (MSCs, a term first coined in Caplan [1991]) can be traced to classical experiments demonstrating that transplantation ofbone marrow (BM) to heterotopic anatomical sites results in de novo generation of ectopic bone and marrow. Whereas examples of such studies date back to the 19th century (Goujon, 1869), the work of Tavassoli and Crosby clearly established proof of an inherent osteogenic potential associated with BM (Tavassoli and Crosby, 1968). Because these experiments were conducted with entire fragments ofbone-free BM, the precise identity of any cell functioning as a progenitor of differentiated bone cells (and therefore of nonhematopoietic, mesenchymal cells) could not be delineated. It was Friedenstein and coworkers, in a series of seminal studies in the 1960s and 1970s (reviewed in Friedenstein, 1990), who demonstrated that the osteogenic potential, as revealed by heterotopic transplantation of BMcells, was associated with a minor subpopulation of BM cells. These cells were distinguishable from the majority of hematopoietic cells by their rapid adherence to tissue culture vessels and by the fibroblast-like appearance of their progeny in culture, pointing to their origin from the stromal compartment of BM. In addition to establishing BM stroma as the haystack in which to search for theproverbial needle, the work of Friedenstein and coworkers provided a second major breakthrough by showing that seeding of BM cell suspensions at clonal density results in the establishment of discrete colonies initiated by single cells (the colony-forming unit fibroblastic, CFU-Fs [Friedenstein et al., 1970]). The clonal nature of each colony was demonstrated by the linear dependence of colony formationon the number of cells explanted, the use of chromosomal markers, 3H-thymidine labeling, through timelapse photography, and by Poisson distribution statistics (Friedenstein, 1976; Friedenstein et al., 1970, 1974; Gronthos et al., 2003). In vivo transplantation led to the recognition that multiple skeletal tissues (bone, cartilage, adipose tissue, and fibrous tissue) could be experimentally...