Pharmacological rescue of diabetic skeletal stem cell niches

Sci Transl Med. 2017 Jan 11;9(372):eaag2809. 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.

MeSH terms

  • Animals
  • Bone and Bones / pathology
  • Cell Proliferation
  • Cell Separation
  • Diabetes Mellitus, Experimental / pathology
  • Female
  • Femoral Fractures / drug therapy*
  • Flow Cytometry
  • Fracture Healing / drug effects*
  • Hedgehog Proteins / metabolism
  • Hedgehog Proteins / pharmacology*
  • Humans
  • Mesenchymal Stem Cells / cytology*
  • Mice
  • Mice, Inbred C57BL
  • Osteogenesis
  • Signal Transduction
  • Stem Cell Niche*


  • Hedgehog Proteins
  • ihh protein, mouse