Research ArticleBONE REPAIR

Pharmacological rescue of diabetic skeletal stem cell niches

See allHide authors and affiliations

Science Translational Medicine  11 Jan 2017:
Vol. 9, Issue 372, eaag2809
DOI: 10.1126/scitranslmed.aag2809

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Stem cells: The key to boosting bone healing in diabetes

Among a myriad of difficulties, people with diabetes have problems with their bones; after a break, their bones do not heal well. Tevlin et al. use mice to investigate the cause and to devise a solution. In several models of diabetes, skeletal stem cells, which normally multiply to repair a bone injury, failed to do so. The high blood concentrations of TNFα in these diabetic mice inhibited a growth factor within the stem cell niche. The authors succeeded in reversing this deficit; delivery of the missing factor directly to the niche restored the expansion of stem cells after injury and normalized bone healing. Correction of the inhospitable niche environment for skeletal stem cells is a promising approach for this complication of diabetes and perhaps for other stem cell–based diseases.

Abstract

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.

View Full Text