Extracellular vesicles from deciduous pulp stem cells recover bone loss by regulating telomerase activity in an osteoporosis mouse model

• Published in: Stem cell research & therapy Vol. 11; no. 1; p. 296
• Main Authors: Sonoda, Soichiro, Murata, Sara, Nishida, Kento, Kato, Hiroki, Uehara, Norihisa, Kyumoto, Yukari N, Yamaza, Haruyoshi, Takahashi, Ichiro, Kukita, Toshio, Yamaza, Takayoshi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 17.07.2020; BioMed Central; BMC
• Subjects: Analysis; Animal models; Animals; Antibodies; Antigens; Bone loss; Bone marrow; Bone Marrow Cells; Calcium phosphate; Calcium phosphates; Cell culture; Cell differentiation; Cell growth; Dental pulp; Disease; Extracellular Vesicles; Fibroblasts; Human deciduous pulp stem cells; Hydroxyapatite; Mesenchyme; Mice; MicroRNA; miRNA; mRNA; Osteoblastogenesis; Osteoporosis; Osteoporosis - therapy; Ovariectomy; Phenotypes; Post-menopause; Postmenopausal women; Proteins; Ribonuclease; Semaphorins; Stem cell transplantation; Stem Cells; Surgery; Telomerase; Telomerase - genetics; Telomerase activity; Transplantation; Tricalcium phosphate; Trophic factors; United States > US; Japan; Extracellular vesicles; Osteoporosis; MicroRNA; Human deciduous pulp stem cells; Telomerase activity
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-020-01818-0

Systemic transplantation of stem cells from human exfoliated deciduous teeth (SHED) recovers bone loss in animal models of osteoporosis; however, the mechanisms underlying this remain unclear. Here, we hypothesized that trophic factors within SHED-releasing extracellular vesicles (SHED-EVs) rescue osteoporotic phenotype. EVs were isolated from culture supernatant of SHED. SHED-EVs were treated with or without ribonuclease and systemically administrated into ovariectomized mice, followed by the function of recipient bone marrow mesenchymal stem cells (BMMSCs) including telomerase activity, osteoblast differentiation, and sepmaphorine-3A (SEMA3A) secretion. Subsequently, human BMMSCs were stimulated by SHED-EVs with or without ribonuclease treatment, and then human BMMSCs were examined regarding the function of telomerase activity, osteoblast differentiation, and SEMA3A secretion. Furthermore, SHED-EV-treated human BMMSCs were subcutaneously transplanted into the dorsal skin of immunocompromised mice with hydroxyapatite tricalcium phosphate (HA/TCP) careers and analyzed the de novo bone-forming ability. We revealed that systemic SHED-EV-infusion recovered bone volume in ovariectomized mice and improved the function of recipient BMMSCs by rescuing the mRNA levels of Tert and telomerase activity, osteoblast differentiation, and SEMA3A secretion. Ribonuclease treatment depleted RNAs, including microRNAs, within SHED-EVs, and these RNA-depleted SHED-EVs attenuated SHED-EV-rescued function of recipient BMMSCs in the ovariectomized mice. These findings were supported by in vitro assays using human BMMSCs incubated with SHED-EVs. Collectively, our findings suggest that SHED-secreted RNAs, such as microRNAs, play a crucial role in treating postmenopausal osteoporosis by targeting the telomerase activity of recipient BMMSCs.