Bone marrow mesenchymal stem cells: historical overview and concepts

Abstract

This review describes the historical emergence of the concept of bone marrow mesenchymal stem cells (MSCs), summarizing data on Wolf and Trentin's hematopoietic inductive microenvironment; Dexter's hematopoiesis-supportive stromal cells; Friedenstein's osteogenic cells; and Pittenger's trilineal osteoblastic, chondrocytic, and adipocytic precursors; to finally introduce the specific bone marrow mesenchymal stem cells with differentiation potential to four lineages (mesenchymal and vascular smooth muscle lineages), and stromal and immunomodulatory capacities. Two points are the object of detailed discussion. The first point envisions the stem cell attributes (multipotentiality, self-renewal, tissue regeneration, population heterogeneity, plasticity, and lineage priming) compared with that of the paradigmatic hematopoietic stem cell. In the second point, we discuss the possible existence of bone marrow cells with greater differentiation potential, eventually pluripotential cells. The latter point raises the issues of cell fusion, reprogramming, or selection under nonstandardized conditions of rare populations of neuroectodermal origin, or of cells that had undergone mesenchymal-to-epithelial transition. In the last section, we review data on MSC senescence and possible malignant transformation secondary to extensive culture, gene transfer of telomerase, or mutations such as leading to Ewing's sarcoma. The set of data leads to the conclusion that bone marrow MSCs constitute a specific adult tissue stem cell population. The multiple characteristics of this stem cell type account for the versatility of the mechanisms of injured tissue repair. Although MSC administration may be extremely useful in a number of clinical applications, their transplantation is not without risks that must not be overlooked when developing cell therapy protocols.

Figure 1. Historical overview

A: The hematopoietic inductive microenvironment of Wolf and Trentin The authors hypothesized that the differentiation pathway of the HSC depends on the territory seeded by HSCs. HSCs seeding non-determined territories do not give rise to colonies (a). HSCs seeding erythroblastic territories (E) give rise to colonies made of maturing red cells; in the shown case the daughter stem cell remains in the same territory, leading to colony size increase (b). HSCs seeding granulocytic territories (G) gives rise to colonies made of maturing granulocytes (c). Large mixed colonies consisting in a mixture of erythroblasts (E), granulocytes (G) and megacaryocytes (M) result from the primary homing of HSC to erythroblastic territory, then migration of daughter HSCs to megakaryocytic and granulocytic territories (d). B) The work of Alexander Friedenstein It can be summarized as follows. I: bone marrow MSC clones (CFU-f) were developed. II: each clone was implanted under the kidney capsule of semi-syngeneic animals; a few weeks after implantation, clones were retrieved and analyzed. III: studies using chimeras revealed that in clones giving rise to bone and marrow, bone cells were of donor origin, while hematopoietic cells were of recipients; the latter probably resulted from homing of circulating blood HSCs and subsequent generation of hematopoietic cells. C) Present view of the HSC niches We hypothesize that the stromal component in osteoblastic niches results from the differentiation of MSCs into osteoblasts, while the stromal component in vascular niches results from the vascular smooth muscle differentiation of the MSCs.

Figure 2. The MSC in its context

There is no precise information on the location of the MSCs in the marrow logettes; what is known is their progeny: osteoblasts, abluminal cells in the marrow sinuses and adipocytes. The 3 major properties of the MSC are emphasized: stemness, stromal capacity (stroma) and immunosuppressive potential (immunosuppression).