Engraftment of skeletal progenitor cells by bone directed transplantation improves osteogenesis imperfecta murine bone phenotype,STEM CELLS

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Engraftment of skeletal progenitor cells by bone directed transplantation improves osteogenesis imperfecta murine bone phenotype
STEM CELLS ( IF 4.0 ) Pub Date : 2019-12-20 , DOI: 10.1002/stem.3133
Benjamin P Sinder ₁ , Sanja Novak ₁ , Natalie K Y Wee ₁ , Mariangela Basile ₁ , Peter Maye ₁ , Brya G Matthews _{1,

2} , Ivo Kalajzic ₁

Affiliation

Osteogenesis imperfecta (OI) is a genetic disorder most commonly caused by mutations associated with type I collagen, resulting in a defective collagen bone matrix. Current treatments for OI focus on pharmaceutical strategies to increase the amount of defective bone matrix, but do not address the underlying collagen defect. Introducing healthy donor stem cells that differentiate into osteoblasts producing normal collagen in OI patients has the potential to increase bone mass and correct the mutant collagen matrix. In this study, donor bone marrow stromal cells (BMSCs, also known as bone marrow mesenchymal stem cells) expressing both αSMACreERT2/Ai9 progenitor reporter and osteoblast reporter Col2.3GFP were locally transplanted into the femur of OI murine (OIM) mice. One month post‐transplantation, 18% of the endosteal surface was lined by donor Col2.3GFP expressing osteoblasts indicating robust engraftment. Long‐term engraftment in the marrow was observed 3 and 6 months post‐transplantation. The presence of Col1a2‐expressing donor cell‐derived cortical bone matrix was detected in transplanted OIM femurs. Local transplantation of BMSCs increased cortical thickness (+12%), the polar moment of inertia (+14%), bone strength (+30%), and stiffness (+30%) 3 months post‐transplantation. Engrafted cells expressed progenitor markers CD51 and Sca‐1 up to 3 months post‐transplantation. Most importantly, 3 months post‐transplantation donor cells maintained the ability to differentiate into Col2.3GFP+ osteoblasts in vitro, and in vivo following secondary transplantation into OIM animals. Locally transplanted BMSCs can improve cortical structure and strength, and persist as continued source of osteoblast progenitors in the OIM mouse for at least 6 months.

中文翻译：

通过骨定向移植植入骨骼祖细胞改善成骨不全鼠骨表型

成骨不全症 (OI) 是一种遗传性疾病，最常见的原因是与 I 型胶原蛋白相关的突变，导致胶原蛋白骨基质缺陷。目前的 OI 治疗侧重于增加有缺陷骨基质数量的药物策略，但并未解决潜在的胶原蛋白缺陷。在 OI 患者中引入可分化为产生正常胶原蛋白的成骨细胞的健康供体干细胞有可能增加骨量并纠正突变的胶原蛋白基质。在这项研究中，将表达 αSMACreERT2/Ai9 祖报告基因和成骨细胞报告基因 Col2.3GFP 的供体骨髓基质细胞（BMSC，也称为骨髓间充质干细胞）局部移植到 OI 鼠（OIM）小鼠的股骨中。移植后一个月，18% 的骨内膜表面衬有供体 Col2.3GFP 表达的成骨细胞，表明植入很牢固。移植后 3 个月和 6 个月观察到骨髓中的长期植入。在移植的 OIM 股骨中检测到表达 Col1a2 的供体细胞衍生的皮质骨基质的存在。BMSCs 的局部移植增加了移植后 3 个月的皮质厚度 (+12%)、极惯性矩 (+14%)、骨强度 (+30%) 和刚度 (+30%)。移植细胞在移植后 3 个月内表达祖标记 CD51 和 Sca-1。最重要的是，移植后 3 个月的供体细胞在体外和体内二次移植到 OIM 动物后仍能保持分化为 Col2.3GFP+ 成骨细胞的能力。

更新日期：2019-12-20

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