Mesenchymal Stem Cells for Bone Repair and Metabolic Bone Diseases

Mayo Clin Proc. 2009 October; 84(10): 893902.

From the Endocrine Research Unit (A.H.U., S.K.) and Division of Orthopedic Research (J.J.W., M.J.Y.), Mayo Clinic, Rochester, MN

Individual reprints of this article are not available. Address correspondence to Sundeep Khosla, MD, Endocrine Research Unit, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (Email: khosla.sundeep/at/mayo.edu).

Human mesenchymal stem cells offer a potential alternative to embryonic stem cells in clinical applications. The ability of these cells to self-renew and differentiate into multiple tissues, including bone, cartilage, fat, and other tissues of mesenchymal origin, makes them an attractive candidate for clinical applications. Patients who experience fracture nonunion and metabolic bone diseases, such as osteogenesis imperfecta and hypophosphatasia, have benefited from human mesenchymal stem cell therapy. Because of their ability to modulate immune responses, allogeneic transplant of these cells may be feasible without a substantial risk of immune rejection. The field of regenerative medicine is still facing considerable challenges; however, with the progress achieved thus far, the promise of stem cell therapy as a viable option for fracture nonunion and metabolic bone diseases is closer to reality. In this review, we update the biology and clinical applicability of human mesenchymal stem cells for bone repair and metabolic bone diseases.

BMMNC = bone marrow mononuclear cell; BMP = bone morphogenic protein; BMT = bone marrow transplant; ESC = embryonic stem cell; FCS = fetal calf serum; iPSC = induced pluripotent stem cell; MSC = mesenchymal stem cell; OI = osteogenesis imperfecta; TNSALP = tissue nonspecific alkaline phosphatase

Recent advances in stem cell research have prompted development of cell-based therapies for bone repair and treatment of metabolic bone diseases. Stem cells are defined by their ability to self-renew and their totipotency or potential to form cells derived from all 3 germ layers. In contrast, cells with self-renewal capacity but more restricted potential are called progenitor cells or tissue stem cells (eg, hematopoietic stem cells or mesenchymal stem cells [MSCs]). Finding an ideal stem cell for clinical applications with high self-renewal capacity and multipotent potential has been a challenge. In recent years, substantial advances have been made in examining the potential of stem cells, especially human embryonic stem cells (ESCs), in regenerative medicine. The ability of human ESCs to self-renew for prolonged periods without differentiation and, most importantly, their ability to differentiate into a large variety of tissues from all 3 germ layers were first characterized by Thomson et al.1 These unique properties of ESCs, specifically self-renewal and pluripotency, made human ESCs ideal candidates for regenerative medicine.

Initial enthusiasm for human ESCs has been tempered and limited by a number of issues, some of which were predicted on the basis of studies with murine ESCs, which were developed more than a decade earlier. Therapeutic use of human ESCs is complicated by immunologic incompatibility and possible development of malignant neoplasms or teratomas from administered cells.2,3 This complication is further hampered by the legal and ethical issues that surround derivation of ESCs from human embryos and their use in research. Thus, despite the ability of human ESCs to self-renew and to differentiate into many cell types, these controversies have restricted their use for therapeutic purposes and prompted scientists to seek other options, such as examining the potential of adult stem cells for regenerative medicine.

For editorial comment, see page 859

Adult stem cells are present in substantial numbers in many tissues throughout life; however, their frequency decreases with age. Tissues that harbor MSCs or MSC-like cells include blood,4 adipose tissue,5 skin,6 trabecular bone,7 and fetal blood, liver, and lung.8,9 The mesenchymal stem-like cells have also been identified in umbilical cord blood10 and placenta.11 Despite sharing similar characteristics, these MSCs from different sources differ in their differentiation potential and gene expression profile.12 Among the different types of adult stem cells, stem cells harbored in the bone marrow are considered to have the highest multilineage potential13 and have been studied for therapeutic purposes. Bone marrow is known to be a rich environment for many cell types. Among these cells are phenotypically and functionally diverse types of cells, collectively referred to as stromal cells. The MSCs comprise a small fraction (<0.01%) of stromal cells. We review the current literature on the biology and specific characteristics of human MSCs (). We also describe recent advances in the use of systemic human MSC therapy in clinical studies related to fracture nonunion and metabolic bone diseases. We reviewed the PubMed literature using the keyword stem cells. The inclusion criteria were use of MSCs in animal models of bone repair and for clinical applications, especially in fracture nonunion, osteogenesis imperfecta (OI), and hypophosphatasia, as well as embryonic and induced pluripotent stem cells (iPSCs) and their use in clinical applications. Additional articles were obtained by assessment of references in the published reviews.

Developmental hierarchy of stem cells (SCs) and therapeutic potential of human mesenchymal stem cells (MSCs). On fertilization of an egg, a blastocyst forms. The inner cell mass of the blastocyst consists of the most primitive SC or totipotent SC. This ...

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Mesenchymal Stem Cells for Bone Repair and Metabolic Bone Diseases