Adult mammals have lost multi-tissue regenerative capacity, except for the distal digit, which is able to regenerate via mechanisms that remain largely unknown. Here, we show that, after adult mouse distal digit removal, nerve-associated Schwann cell precursors (SCPs) dedifferentiate and secrete growth factors that promote expansion of the blastema and digit regeneration. When SCPs were dysregulated or ablated, mesenchymal precursor proliferation in the blastema was decreased and nail and bone regeneration were impaired. Transplantation of exogenous SCPs rescued these regeneration defects. We found that SCPs secrete factors that promote self-renewal of mesenchymal precursors, and we used transcriptomic and proteomic analysis to define candidate factors. Two of these, oncostatin M (OSM) and platelet-derived growth factor AA (PDGF-AA), are made by SCPs in the regenerating digit and rescued the deficits in regeneration caused by loss of SCPs. As all peripheral tissues contain nerves, these results could have broad implications for mammalian tissue repair and regeneration.

BackgroundThe effects of diet-induced obesity on skeletal muscle function are largely unknown, particularly as it relates to changes in oxidative metabolism and morphology.Principal FindingsCompared to control fed mice, mice fed a high fat diet (HFD; 60% kcal: fat) for 8 weeks displayed increased body mass and insulin resistance without overt fasting hyperglycemia (i.e. pre-diabetic). Histological analysis revealed a greater oxidative potential in the HFD gastrocnemius/plantaris (increased IIA, reduced IIB fiber-type percentages) and soleus (increased I, IIA cross-sectional areas) muscles, but no change in fiber type percentages in tibialis anterior muscles compared to controls. Intramyocellular lipid levels were significantly increased relative to control in HFD gastrocnemius/plantaris, but were similar to control values in the HFD soleus. Using a novel, single muscle fiber approach, impairments in complete palmitate and glucose oxidation (72.8±6.6% and 61.8±9.1% of control, respectively; p<0.05) with HFD were detected. These reductions were consistent with measures made using intact extensor digitorum longus and soleus muscles. Compared to controls, no difference in succinate dehydrogenase or citrate synthase enzyme activities were observed between groups in any muscle studied, however, short-chain fatty acyl CoA dehydrogenase (SCHAD) activity was elevated in the HFD soleus, but not tibialis anterior muscles. Despite these morphological and metabolic alterations, no significant difference in peak tetanic force or low-frequency fatigue rates were observed between groups.ConclusionsThese findings indicate that HFD induces early adaptive responses that occur in a muscle-specific pattern, but are insufficient to prevent impairments in oxidative metabolism with continued high-fat feeding. Moreover, the morphological and metabolic changes which occur with 8 weeks of HFD do not significantly impact muscle contractile properties.

Ankrd11 is a potential chromatin regulator implicated in neural development and autism spectrum disorder (ASD) with no known function in the brain. Here, we show that knockdown of Ankrd11 in developing murine or human cortical neural precursors caused decreased proliferation, reduced neurogenesis, and aberrant neuronal positioning. Similar cellular phenotypes and aberrant ASD-like behaviors were observed in Yoda mice carrying a point mutation in the Ankrd11 HDAC-binding domain. Consistent with a role for Ankrd11 in histone acetylation, Ankrd11 was associated with chromatin and colocalized with HDAC3, and expression and histone acetylation of Ankrd11 target genes were altered in Yoda neural precursors. Moreover, the Ankrd11 knockdown-mediated decrease in precursor proliferation was rescued by inhibiting histone acetyltransferase activity or expressing HDAC3. Thus, Ankrd11 is a crucial chromatin regulator that controls histone acetylation and gene expression during neural development, thereby providing a likely explanation for its association with cognitive dysfunction and ASD.

Krause MP, Riddell MC, Hawke TJ. Effects of type 1 diabetes mellitus on skeletal muscle: clinical observations and physiological mechanisms.