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Allogeneic Mesenchymal Stem Cell Therapy Promotes Osteoblastogenesis and Prevents Glucocorticoid-Induced Osteoporosis.

ABSTRACT:

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: Gene-modified mesenchymal stem cell (MSC)-like cells with enhanced bone marrow homing and osteogenesis have been used in treating glucocorticoid-induced murine osteoporosis (GIOP). Recent preclinical studies have further demonstrated the immunomodulatory and anticatabolic potential of allogeneic MSCs in treating osteoporosis under inflammatory and autoimmune conditions. In this study, we investigated whether systemic infusion of allogeneic MSCs without genetic manipulation could prevent GIOP, whether anabolic and anticatabolic effects existed, and whether homing or immunomodulation underlay the putative therapeutic effects. Allogeneic bone marrow-derived MSCs (BMMSCs) were isolated, identified, and systemically infused into mice treated with excessive dexamethasone. We revealed that allogeneic MSC transplantation prevented the reduction of bone mass and strength in GIOP. Bone histomorphometric analyses of bone remodeling demonstrated the maintenance of bone formation and osteoblast survival after MSC therapy. Using green fluorescent protein (GFP)-labeled BMMSCs, we showed that donor BMMSCs(GFP) homed and inhabited recipient bone marrow for at least 4 weeks and prevented recipient bone marrow cell apoptosis, as shown by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Furthermore, donor BMMSCs(GFP) committed to Osterix (Osx)(+) osteoblast progenitors and induced recipient osteoblastogenesis, as exhibited by GFP-Osx double-labeling immunofluorescence analysis. No anticatabolic effects or systemic immunomodulatory effects of infused BMMSCs were detected. These findings demonstrated that allogeneic MSC therapy prevented GIOP by inhabiting and functioning in recipient bone marrow, which promoted osteoblastogenesis, which in turn maintained bone formation. Our findings provide important information regarding cell-based anabolic therapy for GIOP and uncover MSC behaviors following the homing event.

Significance

This study revealed the therapeutic potential of systemically infused, genetically unmodified allogeneic MSCs in glucocorticoid-induced osteoporosis. The donor MSCs inhabited recipient bone marrow and promoted osteoblastogenesis. The therapeutic effects were based on maintenance of bone formation. These results provide important information regarding cell-based anabolic therapy for glucocorticoid-induced osteoporosis and uncover previously unrecognized mesenchymal stem cell behaviors following a homing event. The current study also indicates that minimizing the time of cell culture confers an advantage for increasing transplanted mesenchymal stem cells to the targeted organ to promote therapeutic effects.

SUBMITTER: Sui B

PROVIDER: S-EPMC4996443 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Allogeneic Mesenchymal Stem Cell Therapy Promotes Osteoblastogenesis and Prevents Glucocorticoid-Induced Osteoporosis.

Sui Bingdong B Hu Chenghu C Zhang Xinyi X Zhao Pan P He Tao T Zhou Cuihong C Qiu Xinyu X Chen Nan N Zhao Xinyi X Jin Yan Y

Stem cells translational medicine 20160630 9

<h4>Unlabelled</h4>: Gene-modified mesenchymal stem cell (MSC)-like cells with enhanced bone marrow homing and osteogenesis have been used in treating glucocorticoid-induced murine osteoporosis (GIOP). Recent preclinical studies have further demonstrated the immunomodulatory and anticatabolic potential of allogeneic MSCs in treating osteoporosis under inflammatory and autoimmune conditions. In this study, we investigated whether systemic infusion of allogeneic MSCs without genetic manipulation c ...[more]

PMID: 27365487

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Project description:BackgroundNitrate, a key component of saliva, has been shown widely physiological functions in the human body. But its function on bone metabolism remains unclear. The aim of this study was to investigate the function and mechanism of saliva nitrate on osteoporosis and the function of bone marrow mesenchymal stem cells (BMSCs).MethodsSaliva nitrate removal or supplemental interventions were performed for 1 month in ovariectomized (OVX) osteopenia mice. The nitrate levels in saliva and serum were detected. The bone formation and bone microarchitecture in the OVX mouse model were investigated by quantitative Micro--computed tomography imaging, histological staining and serum bone biomarker analysis. The effects of nitrate on the functional homeostasis of BMSCs in OVX mice were explored by Ki67 immunofluorescence staining, Ki67 flow staining, alizarin red staining, qPCR and western blotting. Finally, downstream signaling pathways were screened by proteomics and verified by western blotting.ResultsThe results showed that nitrate deficiency exacerbated osteoporosis, while nitrate administration prevent osteoporosis in OVX mice. Nitrate increased the expression of PINP, a biomarker of bone formation, in OVX mice. Besides, nitrate enhanced the proliferative capacity and osteogenic function of BMSCs in OVX mice in vitro and in vivo. In addition, nitrate upregulated the expression levels of osteogenesis-related genes ALP, Run2 and OPN of BMSCs. EGFR and mTOR signaling were screened as the key downstream of nitrate, and phosphorylated protein levels of its subfamily members AKT, ERK and S6K were significantly upregulated by nitrate.ConclusionThe present results showed saliva nitrate preventively protects against osteoporosis through enhances the proliferation and osteogenic differentiation potential of BMSCs. The effects of nitrate on bone homeostasis are closely related to the EGFR/AKT/ERK and mTOR/S6K signaling axes.The translational potential of this articleOur study provides experimental evidence for the use of saliva nitrate as an effective candidate for the prevention of osteoporosis and maintenance of bone homeostasis.

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Project description:UnlabelledWe profiled the global gene expression of a bone marrow-derived mesenchymal pluripotent cell line in response to Runx2 expression. Besides osteoblast differentiation, Runx2 promoted the osteoclastogenesis of co-cultured splenocytes. This was attributable to the upregulation of many novel osteoclastogenic genes and the downregulation of anti-osteoclastogenic genes.IntroductionIn addition to being a master regulator for osteoblast differentiation, Runx2 controls osteoblast-driven osteoclastogenesis. Previous studies profiling gene expression during osteoblast differentiation had limited focus on Runx2 or paid little attention to its role in mediating osteoblast-driven osteoclastogenesis.MethodsST2/Rx2(dox), a bone marrow-derived mesenchymal pluripotent cell line that expresses Runx2 in response to Doxycycline (Dox), was used to profile Runx2-induced gene expression changes. Runx2-induced osteoblast differentiation was assessed based on alkaline phosphatase staining and expression of classical marker genes. Osteoclastogenic potential was evaluated by TRAP staining of osteoclasts that differentiated from primary murine splenocytes co-cultured with the ST2/Rx2(dox) cells. The BeadChip™ platform (Illumina) was used to interrogate genome-wide expression changes in ST2/Rx2(dox) cultures after treatment with Dox or vehicle for 24 or 48 h. Expression of selected genes was also measured by RT-qPCR.ResultsDox-mediated Runx2 induction in ST2 cells stimulated their own differentiation along the osteoblast lineage and the differentiation of co-cultured splenocytes into osteoclasts. The latter was attributable to the stimulation of osteoclastogenic genes such as Sema7a, Ltc4s, Efnb1, Apcdd1, and Tnc as well as the inhibition of anti-osteoclastogenic genes such as Tnfrsf11b (OPG), Sema3a, Slco2b1, Ogn, Clec2d (Ocil), Il1rn, and Rspo2.ConclusionDirect control of osteoblast differentiation and concomitant indirect control of osteoclast differentiation, both through the activity of Runx2 in pre-osteoblasts, constitute a novel mechanism of coordination with a potential crucial role in coupling bone formation and resorption.

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Allogeneic Mesenchymal Stem Cell Therapy Promotes Osteoblastogenesis and Prevents Glucocorticoid-Induced Osteoporosis.

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Publications

Allogeneic Mesenchymal Stem Cell Therapy Promotes Osteoblastogenesis and Prevents Glucocorticoid-Induced Osteoporosis.

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