Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

Skeletal stem and progenitor cells(SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

Small extrachromosomal circular DNA in amyotrophic lateral sclerosis matter

Comprehensive studies identify motor neuron spectrum disorders including amyotrophic lateral sclerosis(ALS)as globally rising fatal disorders with the highest prevalence in aging populations,influenced by ethnicity and ancestry(GBD 2016 Motor Neuron Disease Colla borators,2018).While~10% of diagnoses involve a family history(fALS),most cases are considered sporadic(sALS).However,population-based studies suggest that even cases without a common index mutation impart heritability(Ryan et al.,2019),indicating a crucial role of rare and as yet unknown genetic denominators.

Inhibition of BET selectively eliminates undifferentiated pluripotent stem cells

Embryonic stem cells （ESCs） maintain their cellular identity through the systematic regulation of master transcription factors and chromatin remodeling complexes. Recent work has shown that the unusually large-scale enhancers-namely super-enhancers （SEs）, on which BRD4, a member of the bromodomain and extraterminal domain （BET） family is highly enriched-could regulate pluripotency-related transcrip- tion factors. Moreover, inhibition of BRD4 binding on SEs has been shown to induce the differentiation of ESCs. However, the underlying mechanism of BRD4 inhibition-mediated stern cell differentiation remains elusive. Here we show that both mouse and human ESCs lose their capacity for self-renewal upon treat- ment with JQ1, a selective inhibitor of BET family including BRD4, with rapid suppression of pluripotency-associated genes. Notably, a high concentration of JQI could selectively eliminate ESCs via apoptosis, without affecting the functionality of differentiated somatic cells from ESCs, suggesting that inhibition of BET may have a beneficial effect on the development of pluripotent stem cell-based cell therapy.

Role of Oct4 in the early embryo development

Oct4 is a key component of the pluripotency regulatory network,and its reciprocal interaction with Cdx2 has been shown to be a determinant of either the self-renewal of embryonic stem cells(ESCs)or their differentiation into trophoblast.Oct4 of maternal origin is postulated to play critical role in defining totipotency and inducing pluripotency during embryonic development.However,the genetic elimination of maternal Oct4 using a Cre-lox approach in mouse revealed that the establishment of totipotency in maternal Oct4–depleted embryos was not affected,and that these embryos could complete full-term development without any obvious defect.These results indicate that Oct4 is not essential for the initiation of pluripotency,in contrast to its critical role in maintaining pluripotency.This conclusion is further supported by the formation of Oct4-GFP–and Nanog-expressing inner cell masses(ICMs)in embryos with complete inactivation of both maternal and zygotic Oct4 expression and the reprogramming of fibroblasts into fully pluripotent cells by Oct4-deficient oocytes.