Review
Circulating mesenchymal stem cells

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Abstract

Mesenchymal precursor cells (MPCs) are multipotent cells capable of differentiating into various mesenchymal tissues, such as bone, cartilage, fat, tendon and muscle. They are present within both mesenchymal tissues and the bone marrow (BM). If marrow-derived MPCs are to have a role in repair and fibrosis of mesenchymal tissues, transit of these cells through the peripheral blood is to be expected. Although there is evidence for the existence of MPCs within the peripheral blood, results are debated and are not always reproducible. Variations in the methods of cell purification, culture and characterisation may explain the inconsistent results obtained in different studies.

Introduction

The study of adult type stem cells is a hot subject, because of the insights they offer into the understanding of tissue repair and regeneration, and also because they represent a possible alternative to embryonic stem (ES) cells in various therapeutic applications. Although haematopoietic stem cells are the best characterised, adult organisms contain several other types such as neural, epithelial and mesenchymal stem cells (MSCs). As will be discussed below, MSCs are found both in mesenchymal tissues and within the bone marrow (BM). Recent investigations have shown that after systemic infusion, marrow-derived MSCs engraft within multiple tissues of mesenchymal origin in the adult organism (Pereira et al., 1995, Prockop, 1997). How bone marrow-derived MSCs gain access to mesenchymal tissues, and whether they play a role in physiological turnover of these tissues, remains unknown. Transit of the MSCs through the peripheral blood would be expected to bridge the gap between the bone marrow and the mesenchymal tissues in need of repair. This article reviews current data on the existence of such a population of circulating MSCs.

Section snippets

What are mesenchymal stem cells?

Excellent reviews of mesenchymal stem cells have already been published (Minguell, Erices, & Conget, 2001), but a brief summary will be provided here.

“Mesenchyme” designates the developing loose connective tissue of an embryo, mainly derived from the mesoderm, and giving rise to a large part of the cells of the connective tissue in the adult. The definition is generally extended to include connective tissue cells in adult tissues such as (myo)fibroblasts, bone, cartilage, fat, tendon, muscles,

Do mesenchymal progenitor cells circulate in the peripheral blood?

Several studies address this issue by attempting to isolate MPCs from peripheral blood using culture conditions similar to those defined for bone marrow-derived MPCs, in either adult or fetal organisms. These studies, which show conflicting results, will be described first.

Other studies have examined the fate of marrow-derived cells after systemic infusion. The engraftment of these cells in various mesenchymal tissues provides indirect evidence for circulating MPCs. Similarly, so does the

Transplantation studies

As already mentioned above, in vivo experiments involving bone marrow transplantation and solid organ transplantation can provide indirect evidence for the existence of circulating MPCs.

Circulating BM-derived endothelial precursor cells (hemangioblasts)

If there is good evidence that bone marrow-derived cells can circulate and seed many tissues and organs, what of the possibility that these same, or similar, cells can also seed new or existing endothelium? The answer, broadly, is yes, and recent evidence is becoming stronger that this is a frequent event under certain circumstances. For example, it has been shown in vitro that cells derived from fetal bone marrow can differentiate into endothelial and haemopoietic cells (Guo et al., 2003). In

Do circulating MAPCs exist?

A subset of marrow cells that co-purify with MPCs, termed multipotent adult progenitor cells (MAPCs) appear to have considerable plasticity, in that, in addition to generating mesenchymal cell types, they are also able to give rise to endothelial cells, neural cells and epithelial cells in vitro under defined culture conditions (Jiang et al., 2002a, Reyes et al., 2001). MAPCs have been purified from human, murine or rat bone marrow mononuclear cells. In vivo after injection into blastocysts,

Conclusions

Mesenchymal stem cells have the potential to be a source of multipotent cells for autologous cell and gene therapy. Following isolation, purification and possibly in vitro differentiation, MPCs could be injected for local cell therapy in patients with damaged bone, cartilage or tendon (Minguell et al., 2001). Genetically modified MPCs could also be used to replace dysfunctional mesenchymal cells, as suggested in the study by Horwitz et al. mentioned earlier (Horwitz et al., 1999). Adult bone

Acknowledgements

Dr. Candice Roufosse is supported by a Clinical Research Fellowship Grant from the Wellcome Trust.

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