TY - JOUR
T1 - Pharmacological rescue of diabetic skeletal stem cell niches
AU - Tevlin, Ruth
AU - Seo, Eun Young
AU - Marecic, Owen
AU - McArdle, Adrian
AU - Tong, Xinming
AU - Zimdahl, Bryan
AU - Malkovskiy, Andrey
AU - Sinha, Rahul
AU - Gulati, Gunsagar
AU - Li, Xiyan
AU - Wearda, Taylor
AU - Morganti, Rachel
AU - Lopez, Michael
AU - Ransom, Ryan C.
AU - Duldulao, Christopher R.
AU - Rodrigues, Melanie
AU - Nguyen, Allison
AU - Januszyk, Michael
AU - Maan, Zeshaan
AU - Paik, Kevin
AU - Yapa, Kshemendra Senarath
AU - Rajadas, Jayakumar
AU - Wan, Derrick C.
AU - Gurtner, Geoffrey C.
AU - Snyder, Michael
AU - Beachy, Philip A.
AU - Yang, Fan
AU - Goodman, Stuart B.
AU - Weissman, Irving L.
AU - Chan, Charles K.F.
AU - Longaker, Michael T.
N1 - Publisher Copyright:
© The Authors 2017.
PY - 2017/1/11
Y1 - 2017/1/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85010701132
U2 - 10.1126/scitranslmed.aag2809
DO - 10.1126/scitranslmed.aag2809
M3 - Article
C2 - 28077677
AN - SCOPUS:85010701132
SN - 1946-6234
VL - 9
JO - Science translational medicine
JF - Science translational medicine
IS - 372
M1 - eaag2809
ER -