Aging of the vasculature, which is integral to the functioning of literally all human organs, serves as a fundamental physiological basis for age-related alterations as well as a shared etiological mechanism for various chronic diseases prevalent in the elderly population. China, home to the world’s largest aging population, faces an escalating challenge in addressing the prevention and management of these age-related conditions. To meet this challenge, the Aging Biomarker Consortium of China has developed an expert consensus on biomarkers of vascular aging (VA) by synthesizing literature and insights from scientists and clinicians. This consensus provides a comprehensive assessment of biomarkers associated with VA and presents a systemic framework to classify them into three dimensions: functional, structural, and humoral. Within each dimension, the expert panel recommends the most clinically relevant VA biomarkers. For the functional domain, biomarkers reflecting vascular stiffness and endothelial function are high-lighted. The structural dimension encompasses metrics for vascular structure, microvascular structure, and distribution. Additionally, proinflammatory factors are emphasized as biomarkers with the humoral dimension. The aim of this expert consensus is to establish a foundation for assessing the extent of VA and conducting research related to VA, with the ultimate goal of improving the vascular health of the elderly in China and globally.
Stem cell-based regenerative therapies, which harness the self-renewal and differentiation properties of stem cells, have been in the spotlight due to their widespread applications in treating degenerative, aging, and other, generally intractable diseases. Therapeutically effective hematopoietic stem cells, mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells have been used in numerous basic and translational studies with exciting results. However, pre-/post-transplantation issues of poor cell survival and retention, uncontrolled differentiation, and insufficient numbers of cells engrafted into host tissues are the major challenges in stem cell-based regenerative therapies. Engineered biomaterials have adjustable biochemical and biophysical properties that significantly affect cell behaviors, such as cell engraftment, survival, migration, and differentiation outcomes, thereby enhancing the engraftment of implanted stem cells and guiding tissue regeneration. Therefore, the combination of stem cell biology with bioengineered materials is a promising strategy to improve the therapeutic outcomes of stem cell-based regenerative therapy. In this review, we summarize the advances in the modulation of behaviors of stem cells via engineered biomaterials. We then present different approaches to harnessing bioengineered materials to enhance the transplantation of stem cells. Finally, we will provide future directions in regenerative therapy using stem cells.
Ulcerative colitis (UC) is a chronic inflammatory disease of colon, which is characterized by cryptarchitectural distortion. Alternation of colonic stem cell (CoSC) contributed to the occurrence of UC, yet the regulatory mechanisms remain unclear. To investigate the dysregulation of transcriptional and post-transcriptional regulation, we performed RNA-seq, ATAC-seq, and m6A meRIP-seq analysis of the cultured CoSCs that were isolated from UC patients. The transcriptome analysis revealed distinct expression signatures of UC patients in mild and severe stages. We observed abnormal activation of immune and extracellular matrix-related genes in patients affected by severe UC. The chromatin accessibility at the promoter regions of these genes was also specifically increased in the severe stage. In addition, we identified that a global loss of RNA m6A modification in the severe stage was accompanied by higher expression of the m6A demethylase FTO. The aberrant activation of a large number of immune and extracellular matrix-related genes, including IL4R, HLA-DPA1, and COL6A1, was related to both the gain of chromatin accessibility and the loss of m6A in severe UC patients. Our finding revealed an environment-independent immune activation of CoSCs in UC and provided FTO as a potential therapeutic target.
Regulation of totipotency and naïve pluripotency is crucial for early human embryo development. However, the mechanisms of naïve pluripotency and totipotency regulation in humans, especially the signaling pathways involved in these processes, remain largely unknown. Here, using the conversion of human extended pluripotent stem cells (hEPSCs) to naïve pluripotent stem cells as a model, we performed a CRISPR/Cas9-based kinome knockout screen to analyze the effect of disrupting 763 kinases in regulating human naïve pluripotency. Further validation using small molecules revealed that the inhibition of ErbB family kinases promoted the transition of hEPSCs to human naïve pluripotent stem cells. More importantly, chemical inhibition of the ErbB family also promoted induction of totipotent signatures in human pluripotent cells under different culture conditions. Our findings provide new mechanistic insights into the regulation of naïve pluripotency and totipotency in humans.
Adult skeletal muscle stem cells (MuSCs) are essential for muscle homeostasis and regeneration. During aging, the number of MuSCs and their regenerative capacity gradually decline but the underlying mechanisms remain elusive. Here, we identify Sugt1 (suppressor of G2 allele of SKP1 homolog), which is a chaperone for kinetochore function during mitosis and is essential for muscle regeneration by regulating MuSC proliferation. Sugt1 expression level is low in quiescent MuSCs but highly induced when the cells become activated and expand as proliferating myoblasts. Inducible inactivation of Sugt1 in MuSCs causes impaired muscle regeneration upon acute injury by impairing MuSC proliferation. Furthermore, loss of Sugt1 leads to cell cycle arrest in the G2/M phase and cellular senescence. Moreover, long-term loss of Sugt1 in MuSCs results in precocious muscle aging by inhibiting MuSC cell proliferation and promoting cellular senescence. Mechanistically, we identify a cytosolic E3 ubiquitin-ligase, Trim21 as a protein interacting partner for Sugt1 in myoblast cells. We further demonstrate that Sugt1 promotes the ubiquitination of p21 via Trim21; and Sugt1 loss causes p21 accumulation to inhibit cell cycle progression and stimulates cellular senescence. Collectively, our findings uncover that Sugt1 is an essential regulator for MuSC regenerative function during muscle regeneration and aging.