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

Abstract

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. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1238-1246 SIGNIFICANCEThis 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.

Recipient Glycemic Micro-environments Govern Therapeutic Effects of Mesenchymal Stem Cell Infusion on Osteopenia

“…S2A-D), and were in accordance with surface profiles currently recognized to represent MSCs (Fig. S2E) 8, 23, 42. MSCs were infused at D25, at which time point hyperglycemia in T1D mice was stable around 400 mg/dL, as shown previously 25 and here by 3 consecutive quantifications (Fig.…”

“…According to reported data, systemically transplanted MSCs rescue bone loss through either circulatory immunomodulation/anti-inflammation 7 or local effects via homing to recipient bone marrow post infusion 8, 9. In this study, we confirmed that infused MSCs existed in recipient circulation for less than 24 h by using MSCs from GFP-transgenic donor mice (Fig.…”

“…Also in an inflammation-induced osteopenia, the OVX model, previous findings have shown that immunomodulation of MSCs to induce T-cell apoptosis via Fasl is indispensable for their therapeutic effects 7. Nevertheless, in the anti-inflammatory drug glucocorticoid-induced osteoporosis, homing of infused MSCs is pivotal while no immunomodulatory was observed, as stated in our previous report 8. The above findings collectively indicate that therapeutic effects of MSCs are micro-environment-dependent; the efficacy differs in organ- and disease- specific patterns upon differential systemic and local niches (for diabetes) and upon different systemic conditions (for osteoporosis).…”

Anti‐aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application

“…Immunofluorescent staining was performed according to our previous work (Sui et al ., 2016b). Specimens were fixed overnight with 4% paraformaldehyde, cryoprotected with 30% sucrose, embedded in the optimal cutting temperature compound, snap‐frozen, and sectioned into 15‐μm sagittal sections (CM1950, Leica, Solms, Germany).…”

Dynamic expression of SMAD3 is critical in�osteoblast differentiation of PDMCs

“…Pharmacokinetic studies have indicated that ~50% of the alendronate absorbed into the body binds to bone surface, while the other 50% is rapidly excreted from the kidneys (20,23,24). Besides conventional chemical therapy, stem cell therapy has been demonstrated to lead to an improvement in patients with osteoporosis by promoting osteo-in patients with osteoporosis by promoting osteo-by promoting osteogenesis and preventing the progression of osteoporosis (25,26). We previously isolated a population of multipotent cells from a human full-term placenta, termed placenta-derived multipotent cells (PDMCs), which were able to differentiate into a range of cell types, including cells with an osteoblastic phenotype (27).…”