Skeletal stem cells (SSCs) are tissue-specific stem cells that can self-renew and sit at the apex of their differentiation hierarchy, giving rise to mature skeletal cell types required for bone growth, maintenance, and repair. Dysfunction in SSCs is caused by stress conditions like ageing and inflammation and is emerging as a contributor to skeletal pathology, such as the pathogenesis of fracture nonunion. Recent lineage tracing experiments have shown that SSCs exist in the bone marrow, periosteum, and resting zone of the growth plate. Unraveling their regulatory networks is crucial for understanding skeletal diseases and developing therapeutic strategies. In this review, we systematically introduce the definition, location, stem cell niches, regulatory signaling pathways, and clinical applications of SSCs.
Skeletal stem cells (SSCs) were originally discovered in the bone marrow stroma. They are capable of self-renewal and multilineage differentiation into osteoblasts, chondrocytes, adipocytes, and stromal cells. Importantly, these bone marrow SSCs localize in the perivascular region and highly express hematopoietic growth factors to create the hematopoietic stem cell (HSC) niche. Thus, bone marrow SSCs play pivotal roles in orchestrating osteogenesis and hematopoiesis. Besides the bone marrow, recent studies have uncovered diverse SSC populations in the growth plate, perichondrium, periosteum, and calvarial suture at different developmental stages, which exhibit distinct differentiation potential under homeostatic and stress conditions. Therefore, the current consensus is that a panel of region-specific SSCs collaborate to regulate skeletal development, maintenance, and regeneration. Here, we will summarize recent advances of SSCs in long bones and calvaria, with a special emphasis on the evolving concept and methodology in the field. We will also look into the future of this fascinating research area that may ultimately lead to effective treatment of skeletal disorders.
Aging is a major risk factor for multiple diseases, including cardiovascular diseases, neurodegenerative disorders, osteoarthritis, and cancer. It is accompanied by the dysregulation of stem cells and other differentiated cells, and the impairment of their microenvironment. Cell therapies to replenish the abovementioned cells provide a promising approach to restore tissue homeostasis and alleviate aging and aging-related chronic diseases. Importantly, by leveraging gene editing technologies, genetic enhancement, an enhanced strategy for cell therapy, can be developed to improve the safety and efficacy of transplanted therapeutic cells. In this review, we provide an overview and discussion of the current progress in the genetic enhancement field, including genetic modifications of mesenchymal stem cells, neural stem cells, hematopoietic stem cells, vascular cells, and T cells to target aging and aging-associated diseases. We also outline questions regarding safety and current limitations that need to be addressed for the continued development of genetic enhancement strategies for cell therapy to enable its further applications in clinical trials to combat aging-related diseases.
Macrophages are widely distributed in various metabolic tissues/organs and play an essential role in the immune regulation of metabolic homeostasis. Macrophages have two major functions: adaptive defenses against invading pathogens by triggering inflammatory cytokine release and eliminating damaged/dead cells via phagocytosis to constrain inflammation. The pro-inflammatory role of macrophages in insulin resistance and related metabolic diseases is well established, but much less is known about the phagocytotic function of macrophages in metabolism. In this review, we review our current understanding of the ontogeny, tissue distribution, and polarization of macrophages in the context of metabolism. We also discuss the Yin-Yang functions of macrophages in the regulation of energy homeostasis. Third, we summarize the crosstalk between macrophages and gut microbiota. Lastly, we raise several important but remain to be addressed questions with respect to the mechanisms by which macrophages are involved in immune regulation of metabolism.
Liver fibrogenesis is a highly dynamic and complex process that drives the progression of chronic liver disease toward liver failure and end-stage liver diseases. Despite decades of intense studies, the cellular and molecular mechanisms underlying liver fibrogenesis remain elusive, and no approved therapies to treat liver fibrosis are currently available. The rapid development of single-cell RNA sequencing (scRNA-seq) technologies allows the characterization of cellular alterations under healthy and diseased conditions at an unprecedented resolution. In this Review, we discuss how the scRNA-seq studies are transforming our understanding of the regulatory mechanisms of liver fibrosis. We specifically emphasize discoveries on disease-relevant cell subpopulations, molecular events, and cell interactions on cell types including hepatocytes, liver sinusoidal endothelial cells, myofibroblasts, and macrophages. These discoveries have uncovered critical pathophysiological changes during liver fibrogenesis. Further efforts are urged to fully understand the functional contributions of these changes to liver fibrogenesis, and to translate the new knowledge into effective therapeutic approaches.
During liver development, hepatocytes, and cholangiocytes are concurrently differentiated from common liver progenitor cells and are assembled into hepatobiliary architecture to perform proper hepatic function. However, the generation of functional hepatobiliary architecture from hepatocytes in vitro is still challenging, and the exact molecular drivers of hepatobiliary cell lineage determination is largely unknown. In this study, functional hepatobiliary organoids (HBOs) are generated from hepatocytes. These HBOs contain a bile duct network surrounded by mature hepatocytes and stably maintain hepatic characteristics and function in vitro and upon transplantation in vivo. Morphological transition and expression profile of hepatocyte-derived organoids recapitulate the process of liver development. Gene regulation landscape of hepatocyte-derived organoids reveal that Tead4 and Ddit3 promote the cell fate commitment of liver progenitors to functional cholangiocytes and hepatocytes, respectively. Liver cell fate determination is reversed by inhibiting Tead4 or increasing Ddit3 expression both in vitro and upon transplantation in vivo. Collectively, hepatocyte-derived HBOs reveal the essential transcription drivers of liver hepatobiliary cell lineage determination and represent powerful models for liver development and regeneration.
The clinical applications of MSC therapy have been intensely investigated in acute respiratory distress syndrome. However, clinical studies have fallen short of expectations despite encouraging preclinical results. One of the key problems is that transplanted stem cells can hardly survive in the harsh inflammatory environment. Prolonging the survival of transplanted MSCs might be a promising strategy to enhance the therapeutic efficacy of MSC therapy. Here, we identified Nestin, a class VI intermediate filament, as a positive regulator of MSC survival in the inflammatory microenvironment. We showed that Nestin knockout led to a significant increase of MSC apoptosis, which hampered the therapeutic effects in an LPS-induced lung injury model. Mechanistically, Nestin knockout induced a significant elevation of endoplasmic reticulum (ER) stress level. Further investigations showed that Nestin could bind to IRE1α and inhibit ER stress-induced apoptosis under stress. Furthermore, pretreatment with IRE1α inhibitor 4μ8C improved MSC survival and improved therapeutic effect. Our data suggests that Nestin enhances stem cell survival after transplantation by inhibiting ER stress-induced apoptosis, improving protection, and repair of the lung inflammatory injury.
The occurrence of obesity is associated with age. But their interplay remains mysterious. Here, we discovered that rotundic acid (RA), a plant-derived pentacyclic triterpene, was a powerful agent for both anti-aging and treating obesity. Considering that obese individuals decrease the appetite-suppressing and energy-expenditure-enhancing functions of leptin leading to obesity, we found RA was a leptin sensitizer, evidenced by observations that RA enhanced the leptin sensitivity to normal diet-induced obese (DIO) mice, and had minimal or no use to normal lean mice, leptin receptor-deficient (db/db) mice, and leptin-deficient (ob/ob) mice. Simultaneously, RA significantly increased energy expenditure, BAT thermogenesis, and glucose metabolism in DIO mice, as the results of enhancing leptin sensitivity. Regarding mode of action, we demonstrated that RA is a noncompetitive inhibitor of leptin negative regulators protein tyrosine phosphatase 1B (PTP1B) and T-cell PTP through interaction with their C-terminus, thus leading to weight loss through enhancing leptin sensitivity. Besides, we showed that deletion of yPTP1 in yeast completely abolished the lifespan extension effect of RA, celstrol, and withaferin A, while these compounds exhibited PTP1B inhibition activity. Furthermore, PTP1B knockdown extend lifespan in yeast and human cells, indicating PTP1B is an important factor regulating cellular aging.
Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disorder threatening the eyesight. The pathogenic mechanisms and biomarkers reflecting disease severity and predicting treatment response require further exploration. Here, we performed a single-cell analysis of peripheral blood mononuclear cells (PBMC) obtained from eight patients with VKH disease and eight healthy controls to comprehensively delineate the changes in VKH disease. We showed a mixture of inflammation, effector, and exhausted states for PBMCs in VKH disease. Notably, our study implicated a newly identified B cell subset, natural killer-like B cells (K-BC) characterized by expressing CD19 and CD56, was correlated with VKH disease. K-BCs expanded in VKH disease, fell back after effective treatment, and promoted the differentiation of pathogenic T cells. Overall, we mapped the peripheral immune cell atlas in VKH disease and indicated the pathogenic role and potential value in predicting treatment response of K-BCs.