Human perivascular stem cells prevent bone graft resorption in osteoporotic contexts by inhibiting osteoclast formation

Abstract

The vascular wall stores mesenchymal progenitor cells which are able to induce bone regeneration, via direct and paracrine mechanisms. Although much is known regarding perivascular cell regulation of osteoblasts, their regulation of osteoclasts, and by extension utility in states of high bone resorption, is not known. Here, human perivascular stem cells (PSCs) were used as a means to prevent autograft resorption in a gonadectomy‐induced osteoporotic spine fusion model. Furthermore, the paracrine regulation by PSCs of osteoclast formation was evaluated, using coculture, conditioned medium, and purified extracellular vesicles. Results showed that PSCs when mixed with autograft bone induce an increase in osteoblast:osteoclast ratio, promote bone matrix formation, and prevent bone graft resorption. The confluence of these factors resulted in high rates of fusion in an ovariectomized rat lumbar spine fusion model. Application of PSCs was superior across metrics to either the use of unpurified, culture‐defined adipose‐derived stromal cells or autograft bone alone. Under coculture conditions, PSCs negatively regulated osteoclast formation and did so via secreted, nonvesicular paracrine factors. Total RNA sequencing identified secreted factors overexpressed by PSCs which may explain their negative regulation of graft resorption. In summary, PSCs reduce osteoclast formation and prevent bone graft resorption in high turnover states such as gonadectomy‐induced osteoporosis.

Panax Notoginseng Saponins Prevent Bone Loss by Promoting Angiogenesis in an Osteoporotic Mouse Model

“…In this study, we applied ovariectomy-induced osteoporosis model [ 21 , 22 ] to verify our hypothesis that PNS could prevent osteoporosis by coactivating osteogenesis and angiogenesis in vivo. After a series of experiments, including serum biochemical analysis, micro-CT morphometry, and histological assessment, we proved that a moderate dose of PNS (40 mg/kg and 80 mg/kg) could prevent bone loss by promoting angiogenesis and osteogenesis.…”

Bone-Forming Perivascular Cells: Cellular Heterogeneity and Use for Tissue Repair

“…34,35 Implanted perivascular cells regenerate bone indirectly via pleiotropic mechanisms, including for example release of extracellular vesicles (EV) 34 as well as nonvesicular paracrine effectors, such as bone morphogenetic proteins. 36 For example, human perivascular EVs induce osteoprogenitor cell proliferation, migration, and osteogenic differentiation to induce bone repair. 34 In contrast, human perivascular cells inhibit osteoclast formation and prevent bone graft resorption via nonvesicular paracrine mechanisms.…”

“…34 In contrast, human perivascular cells inhibit osteoclast formation and prevent bone graft resorption via nonvesicular paracrine mechanisms. 36 Negative regulators of osteoclast differentiation were enriched within perivascular stem cells, including the decoy receptor for RANKL osteoprotegerin (TNRSF11B), the Wnt and RANKL inhibitor secreted frizzled-related protein-1 (SFRP1), anti-osteoclastic/axonal guidance molecules such as semaphorin 3A (SEMA3A), and slit guidance ligand 3 (SLIT3). The relative roles of human adventitial cells and pericytes in bone repair were described recently by our group.…”

“…Perivascular adventitial cells participate directly in bone formation and repair 32,33 as well as indirectly induce bone repair via interaction with native skeletal cells 34,35 . Implanted perivascular cells regenerate bone indirectly via pleiotropic mechanisms, including for example release of extracellular vesicles (EV) 34 as well as nonvesicular paracrine effectors, such as bone morphogenetic proteins 36 . For example, human perivascular EVs induce osteoprogenitor cell proliferation, migration, and osteogenic differentiation to induce bone repair 34 .…”

“…For example, human perivascular EVs induce osteoprogenitor cell proliferation, migration, and osteogenic differentiation to induce bone repair 34 . In contrast, human perivascular cells inhibit osteoclast formation and prevent bone graft resorption via nonvesicular paracrine mechanisms 36 . Negative regulators of osteoclast differentiation were enriched within perivascular stem cells, including the decoy receptor for RANKL osteoprotegerin ( TNRSF11B ), the Wnt and RANKL inhibitor secreted frizzled‐related protein‐1 ( SFRP1 ), anti‐osteoclastic/axonal guidance molecules such as semaphorin 3A ( SEMA3A ), and slit guidance ligand 3 ( SLIT3 ).…”