Pharmacological rescue of diabetic skeletal stem cell niches

被引：89

作者：

Tevlin, Ruth ^{[1
,2
,3
]}

Seo, Eun Young ^{[1
,2
,3
]}

Marecic, Owen ^{[1
,2
,3
]}

McArdle, Adrian ^{[1
,2
,3
]}

Tong, Xinming ^{[4
]}

Zimdahl, Bryan ^{[3
]}

Malkovskiy, Andrey ^{[5
]}

Sinha, Rahul ^{[3
]}

Gulati, Gunsagar ^{[3
]}

Li, Xiyan ^{[6
]}

Wearda, Taylor ^{[1
,2
,3
]}

Morganti, Rachel ^{[3
]}

Lopez, Michael ^{[3
]}

Ransom, Ryan C. ^{[3
]}

Duldulao, Christopher R. ^{[1
,2
]}

Rodrigues, Melanie ^{[1
,2
]}

Nguyen, Allison ^{[3
]}

Januszyk, Michael ^{[1
,2
]}

Maan, Zeshaan ^{[1
,2
]}

Paik, Kevin ^{[1
,2
]}

Yapa, Kshemendra-Senarath ^{[1
,2
]}

Rajadas, Jayakumar ^{[5
]}

Wan, Derrick C. ^{[1
,2
]}

Gurtner, Geoffrey C. ^{[1
,2
]}

Snyder, Michael ^{[6
]}

Beachy, Philip A. ^{[7
,8
]}

Yang, Fan ^{[4
,9
]}

Goodman, Stuart B. ^{[9
]}

Weissman, Irving L. ^{[3
,10
,11
]}

Chan, Charles K. F. ^{[1
,2
,3
,10
,11
]}

Longaker, Michael T. ^{[1
,2
,3
]}

机构：

[1] Stanford Univ, Hagey Lab Pediat Regenerat Med, Palo Alto, CA 94305 USA

[2] Stanford Univ, Dept Surg, Palo Alto, CA 94305 USA

[3] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Palo Alto, CA 94305 USA

[4] Stanford Univ, Dept Bioengn, Palo Alto, CA 94305 USA

[5] Stanford Univ, Dept Biomat & Adv Drug Delivery, Palo Alto, CA 94305 USA

[6] Stanford Univ, Dept Genet, Palo Alto, CA 94305 USA

[7] Stanford Univ, Dept Biochem, Palo Alto, CA 94305 USA

[8] Howard Hughes Med Inst, Stanford, CA 94305 USA

[9] Stanford Univ, Dept Orthopaed Surg, Palo Alto, CA 94305 USA

[10] Stanford Univ, Dept Pathol, Palo Alto, CA 94305 USA

[11] Stanford Univ, Dept Dev Biol, Palo Alto, CA 94305 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2017年 / 9卷 / 372期

关键词：

NECROSIS-FACTOR-ALPHA; BONE-FORMATION; INSULIN-RESISTANCE; TNF-ALPHA; ENDOCHONDRAL OSSIFICATION; FRACTURE; CARTILAGE; OBESITY; DIFFERENTIATION; IDENTIFICATION;

D O I：

10.1126/scitranslmed.aag2809

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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-alpha 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.

引用

页数：11

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