In search of in vivo MSC

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Background

The concept of multipotent mesenchymal stromal cells (MSCs) arose from the work of A.J. Friedenstein and coworkers in which the authors observed that culturing human bone marrow (BM) cell suspensions, in plastic dishes, lead to isolation of proliferating adhered colonies of fribroblastoid cells able to differentiate into chondrocytes or osteoblasts, in vitro [1], and in vivo [2]. Authors firstly described these cells as colony forming units of fibroblastoid cells (CFU-Fs) referring to their ability to form large colonies on plastic surfaces.
The acronymous “MSC” became popular after the work of A.I. Caplan et al in 1991 where the authors proposed that in adult BM, a population of stem cells could differentiate into different tissues originated from the mesodermal layer, during embryonic development [3]. They termed these cells as “mesenchymal stem cells” (MSCs). Later, the multilineage differentiation capability of MSCs was then definitively demonstrated, these cells shown a stable phenotype expressing novel markers as CD105, CD73 and CD90 and could be expanded retaining the ability to differentiate, in vitro, into vary mesodermal tissues [4]. Some investigators described these latest findings as the definitive characterization of the culture expanded CFU-F population originally described by Friedenstein group, but the identity of the putative in vivo MSC remain enigmatic [5].
Emerging interest in identifying the MSCs in vivo counterpart in order to indicate feasible prospective isolation methods lead to increasing number of ex vivo isolating immunological procedures. Nonetheless, any effort failed to describe a definitive and widely accepted protocol, and significantly contributed to the ongoing confusion in the description of the in vivo MSC identity. Meanly, the inconclusive data about isolation of the putative MSC progenitor could be ascribed to the assumption that any marker expressed on culture-expanded MSCs was also likely to be present in vivo. Consequently, independent laboratories have begun to use different markers of cultured MSCs to search for MSCs in the source tissues [6,7,8]. This has resulted in the perception that these in vivo progenitors were highly heterogeneous cell population and that the different protocols applied could lead to the isolation of distinct sub-populations showing increased CFU-F frequencies.
Moreover, a large number of different tissues and organs have been described as feasible source of MSC, contributing to the variability of protocols, sometimes hardly reproducible, and heterogeneity of isolated populations. Defining where the MSCs could be found could significantly help the hunt of the ancestral in vivo MSC progenitor. Some other adult tissue-specific multipotent cells are found in specialized niches in their corresponding tissues of origin. Hematopoietic stem cells reside in the bone marrow [9], neural SCs in the sub-ventricular zone [10], and some others. On the contrary, the main differentiated cell types originated from MSCs are present throughout the entire organism. To date, three hypothesis could explain MSC tissue distribution: 1) MSCs are tissue-resident cells and can be collected from distinct tissues and organs, 2) MSCs reside in some tissues and circulate in blood or 3) MSCs are derived from the circulating blood.
Recently, interesting studies describing new progenitors of the mesodermal lineage [11, 12, 13] alongside investigations on a possible perivascolar origin of MSC [14], contribute to the establishment of new concepts on the in vivo MSC identity.

REFERENCES
1) Friedenstein AJ (1968). Transplantation 6, 23
2) Friedenstein AJ (1974). Transplantation 17, 331
3) Caplan AI (1991). J Ortho Res 9, 641
4) Pittenger MF (1999) Science 284, 143
5) Bianco P (2000) J Clin Invest 105, 1663
6) Simmons PJ (1991) Blood 78, 55

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