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Sci Transl Med. 2017 Jan 11;9(372). pii: eaag2809. doi: 10.1126/scitranslmed.aag2809.

Pharmacological rescue of diabetic skeletal stem cell niches.

Author information

1
Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA.
2
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.
3
Department of Bioengineering, Stanford University, Palo Alto, CA 94305, USA.
4
Department of Biomaterials and Advanced Drug Delivery, Stanford University, Palo Alto, CA 94305, USA.
5
Department of Genetics, Stanford University, Palo Alto, CA 94305, USA.
6
Department of Biochemistry, Stanford University, Palo Alto, CA 94305, USA.
7
Howard Hughes Medical Institute, Stanford, CA 94305, USA.
8
Department of Orthopaedic Surgery, Stanford University, Palo Alto, CA 94305, USA.
9
Departments of Pathology and Developmental Biology, Stanford University, Palo Alto, CA 94305, USA.
10
Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA. chazchan@stanford.edu longaker@stanford.edu.

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.

Comment in

PMID:
28077677
PMCID:
PMC5725192
DOI:
10.1126/scitranslmed.aag2809
[Indexed for MEDLINE]
Free PMC Article

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