Modification of COL1A1 in Autologous Adipose Tissue-Derived Progenitor Cells Rescues the Bone Phenotype in a Mouse Model of Osteogenesis Imperfecta

Abstract

Osteogenesis imperfecta (OI) is a congenital genetic disorder mainly manifested as bone fragility and recurrent fracture. Mutation of COL1A1/COL1A2 genes encoding the type I collagen are most responsible for the clinical patients. Allogenic mesenchymal stem cells (MSCs) provide the potential to treat OI through differentiation into osteoblasts. Autologous defective MSCs have not been utilized in OI treatment mainly because of their impaired osteogenesis, but the latent mechanism has not been well understood. Here, the relative signaling abnormality of adipose‐derived mesenchymal stem cells (ADSCs) isolated from OI type I mice (Col1a1+/−365 mice) was explored. Autologous ADSCs transfected by retrovirus carrying human COL1A1 gene was first utilized in OI therapy. The results showed that decreased activity of Yes‐associated protein (YAP) due to hyperactive upstream Hippo kinases greatly contributed to the weakened bone‐forming capacity of defective ADSCs. Recovered collagen synthesis of autologous ADSCs by COL1A1 gene modification normalized Hippo/YAP signaling and effectively rescued YAP‐mediated osteogenesis. And the COL1A1 gene engineered autologous ADSCs efficaciously improved the microstructure, enhanced the mechanical properties and promoted bone formation of Col1a1+/−365 mice after femoral bone marrow cavity delivery and might serve as an alternative source of stem cells in OI treatment. © 2021 American Society for Bone and Mineral Research (ASBMR).

Improvement of Inflammation and Abnormal Vascularization by TSP1 Treatment Combined with ADSCs Transplantation in Mice with Induced Polycystic Ovary Syndrome

“…MSC administration may promote the restoration of tissue function by inhibiting the production of proinflammatory cytokines such as IL-1𝛽, TNF-𝛼, and IFN-𝛾. [41] Our previous studies demonstrated that ADSCs are superior sources of MSCs [27,42] with potential immunosuppressive and anti-inflammatory effects. [43] It is worth noting that in the presence of other synergistic factors, ADSCs can have a better therapeutic effect.…”

Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches

“…Liu et al utilized retroviral transfection to introduce the human COL1A1 gene into adipocyte-derived MSCs from mice lacking this gene, resulting in significantly increased bone formation in OI animals. 250 Oyama et al retrovirally transfected bone marrow stromal cells into nude mice, demonstrating in vivo expression and bone development after 6 weeks. This technique also enhanced the osteogenic ability when applied to oim mice, suggesting the potential of introducing normal genes into the OI model using these cells as vectors to improve osteogenic potential.…”

“…This approach aims to enhance or correct gene mutations leading to protein dysfunction. Liu et al utilized retroviral transfection to introduce the human COL1A1 gene into adipocyte-derived MSCs from mice lacking this gene, resulting in significantly increased bone formation in OI animals . Oyama et al retrovirally transfected bone marrow stromal cells into nude mice, demonstrating in vivo expression and bone development after 6 weeks.…”

Mesenchymal stem cells in the treatment of osteogenesis imperfecta

“…Similarly, Liu et al showed that ASCs from OI mice had reduced ALP and collagen levels due to decreased YAP signaling, although they also reported a decrease in colony forming units (CFUs) from ASCs derived from OI mice. They reported that autologous ASCs may be able to divide and differentiate into osteoblasts, however, they will be defective cells that produce minimal or aberrant collagen (Liu et al 2021 ).…”

“…Another study by Liu et al tested if cells from OI mice could be genetically corrected and, therefore, therapeutically effective. They isolated ASCs from OI mice and transfected them with COL1A1 (Liu et al 2021 ). The genetically modified ASCs were able to produce normal type I collagen and were able to differentiate into bone-lineage cells in vitro before re-transplantation to mice.…”