Review
Mesenchymal stem cells: clinical applications and biological characterization

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Abstract

Mesenchymal stem cells (MSCs) have been isolated from bone marrow, periosteum, trabecular bone, adipose tissue, synovium, skeletal muscle and deciduous teeth. These cells have the capacity to differentiate into cells of connective tissue lineages, including bone, fat, cartilage and muscle. A great deal has been learned in recent years about the isolation and characterization of MSCs, and control of their differentiation. These cells have generated a great deal of interest because of their potential use in regenerative medicine and tissue engineering and there are some dramatic examples, derived from both pre-clinical and clinical studies, that illustrate their therapeutic value. This review summarizes recent findings regarding the potential clinical use of MSCs in cardiovascular, neural and orthopaedic applications. As new methods are developed, there are several aspects to the implanted cell–host interaction that need to be addressed before we can fully understand the underlying mechanisms. These include the host immune response to implanted cells, the homing mechanisms that guide delivered cells to a site of injury and the differentiation in vivo of implanted cells under the influence of local signals.

Introduction

Adult human stem cells have been isolated from a wide variety of tissues and, in general, their differentiation potential may reflect the local environment. They lack tissue-specific characteristics but under the influence of appropriate signals can differentiate into specialized cells with a phenotype distinct from that of the precursor. It may be that stem cells in adult tissues are reservoirs of reparative cells, ready to mobilize and differentiate in response to wound signals or disease conditions. Little information is currently available about the biology of endogenous stem cell populations in adults and their precise role in tissue repair or regeneration. This may be due in part to the lack of useful cell-specific markers. What is clear, however, is the ease with which these cells can be isolated and expanded in culture through many generations while retaining the capacity to differentiate. Recent progress in the isolation and characterization of these cells has led to the development and testing of therapeutic strategies in a variety of clinical applications.

Mesenchymal stem cells (MSCs), which reside within the stromal compartment of bone marrow were first identified in the pioneering studies of Friedenstein and Petrakova (1966), who isolated bone-forming progenitor cells from rat marrow. They have the capacity to differentiate into cells of connective tissue lineages, including bone, fat, cartilage and muscle. In addition, they play a role in providing the stromal support system for haematopoietic stem cells in the marrow. MSCs represent a very small fraction, 0.001–0.01% of the total population of nucleated cells in marrow (Pittenger et al., 1999). However, they can be isolated and expanded with high efficiency, and induced to differentiate to multiple lineages under defined culture conditions. These cells have generated a great deal of interest because of their potential use in regenerative medicine and tissue engineering. Both pre-clinical and clinical studies offer dramatic examples that illustrate the therapeutic value of MSCs. While the therapeutic testing of these cells has progressed well, there are still many questions to be addressed concerning the role of endogenous populations of stem cells in the adult, and the function of various stem cell niches. In addition, there are several aspects to the implanted cell–host interaction that need to be addressed as we attempt to understand the mechanisms underlying these therapies. Firstly, host responses to allogeneic MSC therapy need to be defined. Secondly, little is known about the mechanisms that direct homing and engraftment of implanted cells and thirdly, the response of MSCs to local differentiation signals in vivo has not been clarified. This review will describe the characteristics of MSCs, as well as some of the many clinical applications that are currently being evaluated. In the context of cellular therapies, recent information regarding implanted cell–host interactions is discussed.

Section snippets

Isolation and characterization of adult MSCs

MSCs are generally isolated from an aspirate of bone marrow harvested from the superior iliac crest of the pelvis in humans (Digirolamo et al., 1999, Pittenger et al., 1999). MSCs have also been isolated from the tibial and femoral marrow compartments (Murphy et al., 2002; Oreffo, Bord, & Triffitt, 1988), and thoracic and lumbar spine (D’Ippolito, Schiller, Ricordi, Roos, & Howard, 1999). In larger animals (Kadiyala, Young, Thiede, & Bruder, 1997; Murphy, 2003; Ringe et al., 2002, Shake et al.,

Surface markers

Considerable effort has been expended on the identification of specific surface markers for selection, detection and testing of MSC preparations. Several monoclonal antibodies have been raised in an effort to provide reagents for the characterization and isolation of human MSCs. For instance, Stro-1 was identified as an antibody that reacted with non-haematopoietic progenitor bone marrow stromal cells (Simmons & Torok-Storb, 1991). The SB-10 antibody was shown to be reactive with an antigen

Tissue-specific stem cells

Recent reports have provided substantial new insights into stem cell populations in a variety of adult tissues, raising new questions about tissue-specific niches, stem cell mobilization and local differentiation cues. In addition to marrow, other sources of stem cells with mesenchymal potential include periosteum (Fukumoto et al., 2003, Nakahara et al., 1990, Zarnett & Salter, 1989; O’Driscoll, Saris, Ito, & Fitzimmons, 2001), trabecular bone (Noth et al., 2002; Sottile, Halleux, Bassilana,

Differentiation

The differentiation of MSCs into bone, cartilage and fat has been described and characterized by multiple laboratories (Barry et al., 2001, Barry et al., 2001; Bruder et al., 1998, Bruder et al., 1998, Bruder et al., 1998; Bruder et al., 1998, Bruder et al., 1998, Bruder et al., 1998; Digirolamo et al., 1999; Johnstone, Hering, Caplan, Goldberg, & Yoo, 1998; Muraglia, Cancedda, & Quarto, 2000; Pittenger et al., 1999). Osteogenic activation requires the presence of β-glycerol-phosphate, ascorbic

Therapeutic applications

Stem cell therapy involves the transplantation of autologous or allogeneic stem cells into patients, either through local delivery or systemic infusion. There is a precedent in haematopoietic stem cell transplantation, which has been used for some years in the treatment of leukemia and other cancers (Tabbara, Zimmerman, Morgan, & Nahleh, 2002). Some striking examples of the therapeutic use of marrow-derived MSCs have been reported recently. These address a broad spectrum of indications,

Implanted cell–host interactions

The question of the host response to implanted MSCs is critical and receiving attention as these cells are being considered in a variety of clinical applications. There are several aspects to the implanted cell–host interaction that need to be addressed as we attempt to understand the mechanisms underlying stem cell therapies. These are (1) the host immune response to implanted cells, (2) the homing mechanisms that guide delivered cells to a site of injury and (3) differentiation of implanted

Conclusions

Although early pre-clinical and clinical data demonstrate the safety and effectiveness of MSC therapy there are still many questions to be answered surrounding the mechanism of action. Additional information is required concerning the therapeutic efficacy of transplanted cells and the mechanisms of engraftment, homing and in vivo differentiation. There is also a need to carry out appropriately designed toxicology studies to demonstrate the long-term safety of these therapies. The widespread use

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