The RNA-binding protein Musashi2 governs osteoblast-adipocyte lineage commitment by suppressing PPARγsignaling

Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells(BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2(Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling.RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.

Progress in human liver organoids

Understanding the development,regeneration,and disorders of the liver is the major goal in liver biology.Current mechanistic knowledge of human livers has been largely derived from mouse models and cell lines,which fall short in recapitulating the features of human liver cells or the structures and functions of human livers.Organoids as an in vitro system hold the promise to generate organ-like tissues in a dish.Recent advances in human liver organoids also facilitate the understanding of the biology and diseases in this complex organ.Here we review the progress in human liver organoids,mainly focusing on the methods to generate liver organoids,their applications,and possible future directions.

SHANK2 is a frequently amplified oncogene with evolutionarily conserved roles in regulating Hippo signaling

Dysfunction of the Hippo pathway enables cells to evade contact inhibition and provides advantages for cancerous overgrowth.However,for a significant portion of human cancer,how Hippo signaling is perturbed remains unknown.To answer this question,we performed a genome-wide screening for genes that affect the Hippo pathway in Drosophila and cross-referenced the hit genes with human cancer genome.In our screen,Prosap was identified as a novel regulator of the Hippo pathway that potently affects tissue growth.Interestingly,a mammalian homolog of Prosap,SHANK2,is the most frequently amplified gene on 11 q13,a major tumor amplicon in human cancer.Gene amplification profile in this 11q13 amplicon clearly indicates selective pressure for SHANK2 amplification.More importantly,across the human cancer genome,SHANK2 is the most frequently amplified gene that is not located within the Myc amplicon.Further studies in multiple human cell lines confirmed that SHANK2 overexpression causes deregulation of Hippo signaling through competitive binding for a LATS1 activator,and as a potential oncogene,SHANK2 promotes cellular transformation and tumor formation in vivo.In cancer cell lines with deregulated Hippo pathway,depletion of SHANK2 restores Hippo signaling and ceases cellular proliferation.Taken together,these results suggest that SHANK2 is an evolutionarily conserved Hippo pathway regulator,commonly amplified in human cancer and potently promotes cancer.Our study for the first time illustrated oncogenic function of SHANK2,one of the most frequently amplified gene in human cancer.Furthermore,given that in normal adult tissues,SHANK2 s expression is largely restricted to the nervous system,SHANK2 may represent an interesting target for anticancer therapy.

Recent advances in tissue stem cells

Stem cells are undifferentiated cells capable of self-renewal and differentiation,giving rise to specialized functional cells.Stem cells are of pivotal importance for organ and tissue development,homeostasis,and injury and disease repair.Tissue-specific stem cells are a rare population residing in specific tissues and present powerful potential for regeneration when required.They are usually named based on the resident tissue,such as hematopoietic stem cells and germline stem cells.This review discusses the recent advances in stem cells of various tissues,including neural stem cells,muscle stem cells,liver progenitors,pancreatic islet stem/progenitor cells,intestinal stem cells,and prostate stem cells,and the future perspectives for tissue stem cell research.