Mesenchymal stem cells (MSCs) are non-hematopoietic stem cells with the capacity to differentiate into tissues of both mesenchymal and non-mesenchymal origin. MSCs can differentiate into osteoblastic, chondrogenic, and adipogenic lineages, although recent studies have demonstrated that MSCs are also able to differentiate into other lineages, including neuronal and cardiomyogenic lineages. Since their original isolation from the bone marrow, MSCs have been successfully harvested from many other tissues. Their ease of isolation and ex vivo expansion combined with their immunoprivileged nature has made these cells popular candidates for stem cell therapies. These cells have the potential to alter disease pathophysiology through many modalities including cytokine secretion, capacity to differentiate along various lineages, immune modulation and direct cell-cell interaction with diseased tissue. Here we first review basic features of MSC biology including MSC characteristics in culture, homing mechanisms, differentiation capabilities and immune modulation. We then highlight some in vivo and clinical evidence supporting the therapeutic roles of MSCs and their uses in orthopedic, autoimmune, and ischemic disorders.
Mesenchymal stem cells (MSCs) are multipotent progenitors and can differentiate into osteogenic, chondrogenic, and adipogenic lineages. Bone morphogenetic proteins (BMPs) play important roles in stem cell proliferation and differentiation. We recently demonstrated that BMP9 is a potent but less understood osteogenic factor. We previously found that BMP9-induced ectopic bone formation is not inhibited by BMP3. Here, we investigate the effect of BMP antagonist noggin on BMP9-induced osteogenic differentiation. BMP antagonists noggin, chording, gremlin, follistatin, and BMP3 are highly expressed in MSCs, while noggin and follistatin are lowly expressed in more differentiated pre-osteoblast C2C12 cells. BMP9-induced osteogenic markers and matrix mineralization are not inhibited by noggin, while noggin blunts BMP2, BMP4, BMP6, and BMP7-induced osteogenic markers and mineralization. Likewise, ectopic bone formation by MSCs transduced with BMP9, but not the other four BMPs, is resistant to noggin inhibition. BMP9-induced nuclear translocation of Smad1/5/8 is not affected by noggin, while noggin blocks BMP2-induced activation of Smad1/5/8 in MSCs. Noggin fails to inhibit BMP9-induced expression of downstream targets in MSCs. Thus, our results strongly suggest that BMP9 may effectively overcome noggin inhibition, which should at least in part contribute to BMP9's potent osteogenic capability in MSCs. Keywords: BMP9; BMP signaling; mesenchymal stem cells; osteogenic differentiation; TGFb/BMP antagonist Bone morphogenetic proteins (BMPs) are members of the TGFb superfamily, which play an important role in regulating stem cell proliferation and differentiation during development. 1-3 Mesenchymal stem cells (MSCs) are non-hematopoietic multipotent cells and have the capacity to differentiate into multiple tissues. [4][5][6] MSCs can differentiate into osteoblastic, chondrogenic, and adipogenic lineages, 4-6 although it has recently been reported that MSCs are also able to differentiate into other lineages, including neuronal 7-9 and cardiomyogenic 10 lineages. It has been well established that BMPs regulate osteoblast differentiation and subsequent bone formation, 2,3,11 and genetic disruptions of these factors have resulted in skeletal and extraskeletal abnormalities during development. 12 We have conducted a comprehensive analysis of the osteogenic capacity of 14 human BMPs and demonstrated that BMP9 is one of the most potent, yet least characterized BMPs promoting osteogenic differentiation of MSCs both in vitro and in vivo. 3,[13][14][15] We also demonstrated that BMP9 regulates a distinct set of downstream targets in MSCs. 3,[15][16][17][18][19][20] BMPs initiate their signaling by binding to the plasma membrane TGFb type I and type II receptors, leading to the nucleus gene regulation through both BMPR-Smad1/5/8-dependent and Smad-independent pathways. 2, 15 We have demonstrated that ALK1 and ALK2 are required type I receptors for BMP9-induced osteogenic signaling. 21 BMP9 (a.k.a., GDF2) was originally identif...
Mesenchymal progenitor cells (MPCs) are nonhematopoietic multipotent cells capable of differentiating into mesenchymal and nonmesenchymal lineages. While they can be isolated from various tissues, MPCs isolated from the bone marrow are best characterized. These cells represent a subset of bone marrow stromal cells (BMSCs) which, in addition to their differentiation potential, are critical in supporting proliferation and differentiation of hematopoietic cells. They are of clinical interest because they can be easily isolated from bone marrow aspirates and expanded in vitro with minimal donor site morbidity. The BMSCs are also capable of altering disease pathophysiology by secreting modulating factors in a paracrine manner. Thus, engineering such cells to maximize therapeutic potential has been the focus of cell/gene therapy to date. Here, we discuss the path towards the development of clinical trials utilizing BMSCs for orthopaedic applications. Specifically, we will review the use of BMSCs in repairing critical-sized defects, fracture nonunions, cartilage and tendon injuries, as well as in metabolic bone diseases and osteonecrosis. A review of www.ClinicalTrials.gov of the United States National Institute of Health was performed, and ongoing clinical trials will be discussed in addition to the sentinel preclinical studies that paved the way for human investigations.
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