Systemic MSC Transplantation Restores Functional Bone in a Mouse Model of Age-related Osteoporosis

Osteoporosis affects millions of people, and represents a substantial quality of life and economic burden. In human aging, the decline in the number and function of resident bone marrow mesenchymal stromal cells (MSCs) has been widely reported. This has led to the speculation that MSCs are required for the maintenance of skeletal homeostasis, and their loss is associated with age-related osteoporosis. Supporting this etiology, the Sca-1 deficient mouse model of human age-related (type II) osteoporosis demonstrates both decreased MSC self-renewal and expansion, leading to defective maintenance of bone mineral density and bone quality. Therefore, to test the hypothesis that increasing the pool of MSCs could provide therapeutic benefits to patients with type II osteoporosis, we assessed the capacity of transplanted wild type MSCs to rescue osteoporosis in Sca-1-/- mice. Donor MSCs were highly clonogenic and retained high osteogenic activity. Short-term engraftment of DiR labeled MSCs transplanted by intravenous tail vein injection displayed successful engraftment into hind limbs of Sca-1-/- mice for at least 14 days. To assess long-term engraftment, a single bolus of labeled MSCs from male donor mice was transplanted into individual 10-week-old Sca-1-/- females. A half year later, mice were sacrificed and engraftment was assessed. Transplanted Sca-1-/- mice displayed low-level MSC engraftment in the bone marrow and lungs beyond 34 weeks of age. However, histological analyses of trabecular tissue revealed increased bone formation, higher osteoclast numbers, and heterogeneous mineralization indicative of healthier bone in these animals compared to untreated Sca-1-/- controls. Furthermore, MicroCT revealed improved trabecular bone connectivity and a restoration of trabecular anisotropy in mice transplanted with wild type MSCs versus untreated Sca-1-/- controls. Taken together, these results demonstrate that a single systemic transplanted dose of MSCs can reduce the inherent bone formation deficit observed in osteoporotic mice, protect them from progressive reduction in bone quality, and restore functional bone microarchitecture for at least 24 weeks following treatment.Ph.D