Elsevier

Archives of Medical Research

Volume 34, Issue 6, November–December 2003, Pages 565-571
Archives of Medical Research

Review article
Mesenchymal stem cells

https://doi.org/10.1016/j.arcmed.2003.09.007Get rights and content

Abstract

It has become clear that adult mammalian bone marrow contains not one but two ostensibly discrete populations of adult stem cells. The first and by far the most fully characterized are the hematopoietic stem cells responsible for maintaining lifelong production of blood cells. The biological characteristics and properties of the second marrow resident population of stem cells, variously termed bone marrow stromal cells or mesenchymal stem cells, are in contrast much less well understood. In vitro, cultures established from single-cell suspensions of bone marrow from a wide range of mammalian species generate colonies of adherent marrow stromal cells, each derived from a single precursor cell termed a colony-forming unit-fibroblast (CFU-F). Culture conditions have been developed to expand marrow stromal cells in vitro while maintaining the capacity of these cells to differentiate into bone, fat, and cartilage. A significant portion of our current knowledge of this population of cells is based on analysis of the properties of these culture expanded cells, not on the primary colony-initiating cells. In this article, we will focus on methodologies to prospectively isolate stromal progenitors from mouse and human bone marrow and will review current data that suggest stromal progenitors in the bone marrow in situ are associated with the outer surfaces of blood vessels and may share identity with vascular pericytes.

Introduction

The stromal tissue of adult mammalian bone marrow (BM) has traditionally been viewed largely in terms of its well-documented role in supporting hematopoiesis, that is, a tissue whose principle function is to provide a microenvironment within the BM that supports the tightly regulated proliferation, differentiation and maturation of hematopoietic stem cells (HSC) into each of the eight distinct lineages that comprise the hematopoietic system. In marked contrast, the possibility that the stroma of the bone marrow may itself be based on a stem cell model and hence contain multipotent stromal stem cells with the capacity to give rise to each of the differentiated cell lineages found in the marrow stroma, bone, and cartilage has until recently received relatively little attention. However, with rapid progress in this area, it is now clear that stem/progenitor cells for skeletal and stromal tissues of the BM unequivocally exist in multiple mammalian species and that the BM must be viewed as an organ that harbors at least two distinct populations of adult stem cells whose various progeny co-exist in a functionally interdependent manner.

The differentiation capacity of cultured bone marrow-derived stromal cells coupled with the apparent ease of ex vivo culture manipulation has not surprisingly engendered considerable interest in potential therapeutic applications of these cells in a wide range of settings. However, many fundamental aspects of marrow stromal cell biology including the developmental origin of marrow stromal cells, the cellular identity and anatomical location of their precursors, and their in vivo functions remain obscure. In this article, our intention is not to provide a comprehensive review of this now large and rapidly expanding field that has been the subject of a number of recent reviews 1., 2., 3., 4., 5., 6., 7., 8. but to focus specifically on the phenotypic properties of stromal precursor cells and on recent insights into their nature and anatomical location.

Section snippets

Marrow stromal cells

Derived from the Greek στρομα (mattress; anything spread or laid out for sitting on), the term stroma is used to signify the supporting connective tissue associated with the dominant functional tissue (or parenchyma) in an organ. As applied to mammalian bone marrow (BM), the term stroma describes the non-hematopoietic connective tissue elements that provide a system of structural support for developing hemopoietic cells but also of functional support for the process of hemopoiesis through the

Clonogenic marrow stromal progenitors in vitro

Pioneering, but all too often understated, contributions to our understanding of stromal precursor cells were made by Friedenstein, Owen, and colleagues. Seeking to identify the cells in rodent bone marrow responsible for bone formation in ectopic transplant experiments (21), Friedenstein and colleagues demonstrated the growth of colonies of cells morphologically resembling fibroblasts when single cell suspensions of bone marrow are explanted at appropriate cell densities (104−105 cells/cm2) in

Phenotypic characteristics of marrow stromal precursor cells

To date, the majority of information regarding the phenotypic properties of marrow stromal cell progenitors is based on analysis of marrow stromal cells in culture, a population now almost universally described as mesenchymal stem cells (41). In contrast, relatively little is known about the precise phenotypic characteristics of the primary clonogenic stromal precursors in the bone marrow responsible for initiating stromal cell growth in vitro. The rarity of these cells is a major barrier to

The anatomical location of stromal stem cells: identity with vascular pericytes?

A significant obstacle to the study of stromal precursor cells is the lack of precise knowledge regarding their anatomical distribution within the bone marrow. However, a burgeoning body of data from a number of investigators now points toward cells of the vessel wall (vascular smooth muscle cells, pericytes) as the cellular identity of clonogenic stromal precursors. Gronthos et al. in 2003 (50) reported that STRO-1brightVCAM-1+ cells freshly isolated from human BM were a morphologically

Conclusions

The field of marrow stromal cell biology as it specifically pertains to precursor cells for this tissue is an exciting, rapidly moving area of research. This article has of necessity focused on the characteristics of the primary stromal precursors as they exist in the bone marrow, an aspect of the biology of these cells that has been somewhat neglected of late in favor of studies that seek to define the phenotypic properties of culture expanded stromal/mesenchymal stem cells. Considerable

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