Tevlin Ruth, Seo Eun Young, Marecic Owen, McArdle Adrian, Tong Xinming, Zimdahl Bryan, Malkovskiy Andrey, Sinha Rahul, Gulati Gunsagar, Li Xiyan, Wearda Taylor, Morganti Rachel, Lopez Michael, Ransom Ryan C, Duldulao Christopher R, Rodrigues Melanie, Nguyen Allison, Januszyk Michael, Maan Zeshaan, Paik Kevin, Yapa Kshemendra-Senarath, Rajadas Jayakumar, Wan Derrick C, Gurtner Geoffrey C, Snyder Michael, Beachy Philip A, Yang Fan, Goodman Stuart B, Weissman Irving L, Chan Charles K F, Longaker Michael T
Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.
Sci Transl Med. 2017 Jan 11;9(372). doi: 10.1126/scitranslmed.aag2809.
Diabetes mellitus (DM) is a metabolic disease frequently associated with impaired bone healing. Despite its increasing prevalence worldwide, the molecular etiology of DM-linked skeletal complications remains poorly defined. Using advanced stem cell characterization techniques, we analyzed intrinsic and extrinsic determinants of mouse skeletal stem cell (mSSC) function to identify specific mSSC niche-related abnormalities that could impair skeletal repair in diabetic (Db) mice. We discovered that high serum concentrations of tumor necrosis factor-α directly repressed the expression of Indian hedgehog (Ihh) in mSSCs and in their downstream skeletogenic progenitors in Db mice. When hedgehog signaling was inhibited during fracture repair, injury-induced mSSC expansion was suppressed, resulting in impaired healing. We reversed this deficiency by precise delivery of purified Ihh to the fracture site via a specially formulated, slow-release hydrogel. In the presence of exogenous Ihh, the injury-induced expansion and osteogenic potential of mSSCs were restored, culminating in the rescue of Db bone healing. Our results present a feasible strategy for precise treatment of molecular aberrations in stem and progenitor cell populations to correct skeletal manifestations of systemic disease.
糖尿病（DM）是一种常与骨愈合受损相关的代谢性疾病。尽管其在全球范围内的患病率不断上升，但糖尿病相关骨骼并发症的分子病因仍不清楚。我们使用先进的干细胞表征技术，分析了小鼠骨骼干细胞（mSSC）功能的内在和外在决定因素，以确定可能损害糖尿病（Db）小鼠骨骼修复的特定mSSC生态位相关异常。我们发现，高血清浓度的肿瘤坏死因子-α直接抑制了Db小鼠mSSC及其下游骨骼生成祖细胞中印度刺猬因子（Ihh）的表达。当在骨折修复过程中刺猬信号通路被抑制时，损伤诱导的mSSC扩增受到抑制，导致愈合受损。我们通过一种特殊配方的缓释水凝胶将纯化的Ihh精确递送至骨折部位，从而逆转了这种缺陷。在外源性Ihh存在的情况下，损伤诱导的mSSC扩增和成骨潜能得以恢复，最终挽救了Db小鼠的骨愈合。我们的研究结果提出了一种可行的策略，用于精确治疗干细胞和祖细胞群体中的分子异常，以纠正全身性疾病的骨骼表现。
