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.

Smart Hydrogels for the Augmentation of Bone Regeneration by Endogenous Mesenchymal Progenitor Cell Recruitment

“…In the absence of BMP‐2, Sca‐1 + MPCs formed isolated bone nodules and homed to the endosteum (Figure and Figure S2, Supporting Information) comparable to CD146 + human MPCs . These data strongly suggest that trapped Sca‐1 + MPCs contain bone healing‐associated stem and progenitor populations similar to fracture callus‐derived SSCs and could be used to study novel bone healing approaches, including their mobilization to the site of regeneration.…”

Identification of the Human Skeletal Stem Cell

“…Moreover, given the tremendous medical burden imposed by degenerative, neoplastic, post-traumatic and post-surgical skeletal disorders, we believe that identifying the hSSC and elucidating its lineage map will enable the molecular diagnosis and treatment of skeletal diseases (Beyth et al, 2011). Using this approach, we recently showed that even complex skeletal pathologies that arise from systemic diseases like diabetes can be precisely diagnosed and remedied by comparing the molecular phenotype of normal and diseased SSCs (Tevlin et al, 2017). Therefore, we anticipate that further characterization of the hSSC, and the ontogeny of hSSC-derived skeletal progenitors as described here will facilitate the development of patient-specific approaches to diagnosing and reversing diverse types of skeletal disorders.…”

Activation of hedgehog signaling by systemic agonist improves fracture healing in aged mice

“…Previous research has focused on direct application of pharmacologic interventions at the fracture site to increase healing. 28,48 A recent study demonstrated that direct application of SAG, a small molecule Hh pathway agonist, was shown to enhance callus formation in a mouse tibial osteotomy model. 28 However, there are significant clinical drawbacks to therapeutics that require direct administration.…”