title: Pharmacological rescue of diabetic skeletal stem cell niches.
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.
authors.affiliation: 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.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tevlin
authors.affiliation: 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.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Seo
authors.affiliation: 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.
authors.forename: Owen
authors.initials: O
authors.lastname: Marecic
authors.affiliation: 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.
authors.forename: Adrian
authors.initials: A
authors.lastname: McArdle
authors.affiliation: Department of Bioengineering, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Xinming
authors.initials: X
authors.lastname: Tong
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Zimdahl
authors.affiliation: Department of Biomaterials and Advanced Drug Delivery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Malkovskiy
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Sinha
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Gunsagar
authors.initials: G
authors.lastname: Gulati
authors.affiliation: Department of Genetics, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Xiyan
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Taylor
authors.initials: T
authors.lastname: Wearda
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Morganti
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lopez
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Ransom
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Duldulao
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Rodrigues
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Januszyk
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Zeshaan
authors.initials: Z
authors.lastname: Maan
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Paik
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Kshemendra-Senarath
authors.initials: KS
authors.lastname: Yapa
authors.affiliation: Department of Biomaterials and Advanced Drug Delivery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajadas
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Derrick C
authors.initials: DC
authors.lastname: Wan
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Gurtner
authors.affiliation: Department of Genetics, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Department of Biochemistry, Stanford University, Palo Alto, CA 94305, USA.|Howard Hughes Medical Institute, Stanford, CA 94305, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
authors.affiliation: Department of Bioengineering, Stanford University, Palo Alto, CA 94305, USA.|Department of Orthopaedic Surgery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.|Departments of Pathology and Developmental Biology, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA. chazchan@stanford.edu longaker@stanford.edu.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.|Departments of Pathology and Developmental Biology, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Charles K F
authors.initials: CK
authors.lastname: Chan
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine and Department of Surgery, Stanford University, Palo Alto, CA 94305, USA. chazchan@stanford.edu longaker@stanford.edu.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000473:pathology; D049109:Cell Proliferation; D002469:Cell Separation; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D005260:Female; D005264:Femoral Fractures / Q000188:drug therapy*; D005434:Flow Cytometry; D017102:Fracture Healing / Q000187:drug effects*; D053823:Hedgehog Proteins / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis; D015398:Signal Transduction; D055153:Stem Cell Niche
chemical_list: D053823:Hedgehog Proteins; C514061:ihh protein, mouse