Mitochondrial transplantation (MT) is a promising therapeutic strategy that involves introducing healthy mitochondria into damaged tissues to restore cellular function. This approach has shown promise in treating cardiac diseases, such as ischemia-reperfusion injury, myocardial infarction, and heart failure, where mitochondrial dysfunction plays a crucial role. Transplanting healthy mitochondria into affected cardiac tissue has resulted in improved cardiac function, reduced infract size, and enhanced cell survival in preclinical studies. Beyond cardiac applications, MT is also being explored for its potential to address various noncardiac diseases, including stroke, infertility, and genetic mitochondrial disorders. Ongoing research focused on refining techniques for mitochondrial isolation, preservation, and targeted delivery is bolstering the prospects of MT as a clinical therapy. As the scientific community gains a deeper understanding of mitochondrial dynamics and pathology, the development of MT as a clinical therapy holds significant promise. This review provides an overview of recent research on MT and discusses the methodologies involved, including sources, isolation, delivery, internalization, and distribution of mitochondria. Additionally, it explores the effects of MT and potential mechanisms in cardiac diseases, as well as non-cardiac diseases. Future prospects for MT are also discussed.

As the most prevalent type of alternative splicing in animal cells, exon skipping plays an important role in expanding the diversity of transcriptome and proteome, thereby participating in the regulation of diverse physiological and pathological processes such as development, aging, and cancer. Cellular senescence serving as an anti-cancer mechanism could also contribute to individual aging. Although the dynamic changes of exon skipping during cellular senescence were revealed, its biological consequence and upstream regulator remain poorly understood. Here, by using human foreskin fibroblasts (HFF) replicative senescence as a model, we discovered that splicing factor PTBP1 was an important contributor for global exon skipping events during senescence. Down-regulated expression of PTBP1 induced senescence-associated phenotypes and related mitochondrial functional changes. Mechanistically, PTBP1 binds to the third exon of mitochondrial complex I subunit coding gene NDUFV3 and protects the exon from skipping. We further confirmed that exon skipping of NDUFV3 correlates with and partially contributes to cellular senescence and related mitochondrial functional changes upon PTBP1 knockdown. Together, we revealed for the first time that mitochondrial-related gene NDUFV3 is a new downstream target for PTBP1-regulated exon skipping to mediate cellular senescence and mitochondrial functional changes.

Awareness of estrogen’s effects on health is broadening rapidly. The effects of long-term high levels of estrogen on the body involve multiple organs. Here, we used both single-cell chromatin accessibility and RNA sequencing data to analyze the potential effect of estrogen on major organs. The integrated cell map enabled in-depth dissection and comparison of molecular dynamics, cell-type compositions, and cellular heterogeneity across multiple tissues and organs under estrogen stimulation. We also inferred pseudotime cell trajectories and cell–cell communications to uncover key molecular signatures underlying their cellular processes in major organs in response to estrogen. For example, estrogen could induce the differentiation of IFIT3⁺ neutrophils into S100A9⁺ neutrophils involved in the function of endosome-to-lysosome transport and the multivesicular body sorting pathway in liver tissues. Furthermore, through integration with human genome-wide association study data, we further identified a subset of risk genes during disease development that were induced by estrogen, such as AKT1 (related to endometrial cancer), CCND1 (related to breast cancer), HSPH1 (related to colorectal cancer), and COVID-19 and asthma-related risk genes. Our work uncovers the impact of estrogen on the major organs, constitutes a useful resource, and reveals the contribution and mechanism of estrogen to related diseases.

Synthetic organ models such as organoids and organ-on-a-chip have been receiving recognition from administrative agencies. Despite the proven success of organoids in predicting drug efficacy on laboratory scales, their translational advances have not fully satisfied the expectations for both clinical implementation and commercial applications. The transition from laboratory settings to clinical applications continues to encounter challenges. Employing engineering methodologies to facilitate the bridging of this gap for organoids represents one of the key directions for future advancement. The main measures to bridge the gap include environmental and phenotypic recapitulation, 3D patterning, matrix engineering, and multi-modality information acquisition and processing. Pilot whole-process clinical/pharmaceutical applications with fast and standardized organoid models will continuously offer convincing frontline optimization clues and driving forces to the organoid community, which is a promising path to translational organoid technologies.

The advent of single-cell sequencing techniques has not only revolutionized the investigation of biological processes but also significantly contributed to unraveling cellular heterogeneity at unprecedented levels. Among the various methods, single-cell transcriptome sequencing stands out as the best established, and has been employed in exploring many physiological and pathological activities. The recently developed single-cell epigenetic sequencing techniques, especially chromatin accessibility sequencing, have further deepened our understanding of gene regulatory networks. In this review, we summarize the recent breakthroughs in single-cell transcriptome and chromatin accessibility sequencing methodologies. Additionally, we describe current bioinformatic strategies to integrate data obtained through these single-cell sequencing methods and highlight the application of this analysis strategy on a deeper understanding of tumorigenesis and tumor progression. Finally, we also discuss the challenges and anticipated developments in this field.

The secretome is composed of cell surface membrane proteins and extracellular secreted proteins that are synthesized via secretory machinery, accounting for approximately one-third of human protein-encoding genes and playing central roles in cellular communication with the external environment. Secretome protein–protein interactions (SPPIs) mediate cell proliferation, apoptosis, and differentiation, as well as stimulus- or cell-specific responses that regulate a diverse range of biological processes. Aberrant SPPIs are associated with diseases including cancer, immune disorders, and illness caused by infectious pathogens. Identifying the receptor/ligand for a secretome protein or pathogen can be a challenging task, and many SPPIs remain obscure, with a large number of orphan receptors and ligands, as well as viruses with unknown host receptors, populating the SPPI network. In addition, proteins with known receptors/ligands may also interact with alternative uncharacterized partners and exert context-dependent effects. In the past few decades, multiple varied approaches have been developed to identify SPPIs, and these methods have broad applications in both basic and translational research. Here, we review and discuss the technologies for SPPI profiling and the application of these technologies in identifying novel targets for immunotherapy and anti-infectious agents.

SHOC2 is a scaffold protein that activates the RAS-MAPK signal. Our recent study showed that SHOC2 is also a negative regulator of the mTORC1 signal in lung cancer cells. Whether and how SHOC2 differentially regulates the RAS-MAPK vs. the mTORC1 signals in liver cancer remains unknown. Here, we showed that SHOC2 is overexpressed in human liver cancer tissues, and SHOC2 overexpression promotes the growth and survival of liver cancer cells via activation of the RAS-MAPK signal, although the mTORC1 signal is inactivated. SHOC2 knockdown suppresses the growth of liver cancer cells mainly through inactivating the RAS-MAPK signal. Thus, in the cell culture models, SHOC2 regulation of growth is dependent of the RAS-MAPK but not the mTORC1 signal. Interestingly, in a mouse liver cancer model induced by diethylnitrosamine (DEN)-high-fat diet (HFD), hepatocyte-specific Shoc2 deletion inactivates the Ras-Mapk signal but has no effect in liver tumorigenesis. However, in the Pten loss-induced liver cancer model, Shoc2 deletion further activates mTorc1 without affecting the Ras-Mapk signal and promotes liver tumorigenesis. Collectively, it appears that SHOC2 could act as either an oncogene (via activating the MAPK signal) or a tumor suppressor (via inactivating the mTORC1 signal) in the manner dependent of the dominancy of the MAPK vs. mTORC1 signals.

Clinical and preclinical research has demonstrated that iPSC-derived NK (iNK) cells have a high therapeutic potential, yet poor understanding of the detailed process of their differentiation in vitro and their counterpart cell development in vivo has hindered therapeutic iNK cell production and engineering. Here we dissect the crucial differentiation of both fetal liver NK cells and iNK cells to enable the rational design of advanced iNK production protocols. We use a comparative analysis of single-cell RNA-seq (scRNA-seq) to pinpoint key factors lacking in the induced setting which we hypothesized would hinder iNK differentiation and/ or functionality. By analyzing key transcription factor regulatory networks, we discovered the importance of TBX21, EOMES, and STAT5A in the differentiation timeline. This analysis provides a blueprint for further engineering new iPSC lines to obtain iNK cells with enhanced functions. We validated this approach by creating a new line of STAT5A-iPSCs which can be differentiated to STAT5A-expressing macrophages with both NK cell and macrophage features such as perforin production, phagocytosis, and anti-tumor functions.

Aging has ascended to the forefront of scientific exploration, demanding a concerted global focus. The 2024 China Aging Science Conference and International Conference on Aging Biology hosted a panel discussion that brought international experts to delve into the complexities of aging research. The discussion underscores the imperative need for a multidisciplinary approach, integrating reductionist and holistic perspectives to unravel the molecular and epigenetic underpinnings of the aging process. Experts advocate for elucidating aging mechanisms and biomarkers, with a focus on translating scientific discoveries into tangible societal benefits. The discussion also emphasizes the importance of international and interdisciplinary collaborations, calling for more support to innovate for healthy aging and tackle age-related challenges.

The decline in intestinal stem cell (ISC) function is a hallmark of aging, contributing to compromised intestinal regeneration and increased incidence of age-associated diseases. Novel therapeutic agents that can rejuvenate aged ISCs are of paramount importance for extending healthspan. Here, we report on the discovery of Chrysosplenosides I and A (CAs 1 & 2), flavonol glycosides from the Xizang medicinal plant Chrysosplenium axillare Maxim., which exhibit potent anti-aging effects on ISCs. Our research, using Drosophila models, reveals that CAs 1 & 2 treatments not only restrain excessive ISC proliferation, thereby preserving intestinal homeostasis, but also extend the lifespan of aging Drosophila. In aged mouse intestinal organoids, CAs 1 & 2 enhance the growth and budding of intestinal organoids, indicating improved regenerative capacity. Mechanistic investigations show that CAs 1 & 2 exert their effects by activating the peroxisome proliferator-activated receptor-gamma (PPARγ) and concurrently inhibiting the epidermal growth factor receptor (EGFR) signaling pathways. Our findings position CAs 1 & 2 as promising candidates for ameliorating ISC aging and suggest that targeting PPARγ, in particular, may offer a therapeutic strategy to counteract age-related intestinal dysfunction.

Age-induced abnormalities in bone metabolism disrupt the equilibrium between bone resorption and formation. This largely stems from disturbances in bone homeostasis, in which signaling pathways exert a significant regulatory influence. Aging compromises the functionality of the bone marrow mesenchymal stem cells (BMSCs), ultimately resulting in tissue dysfunction and pathological aging. Age-related bone degradation primarily manifests as reduced bone formation and the increased accumulation of bone marrow fat. Cellular senescence diminishes bone cell vitality, thereby disrupting the balance of bone remodeling. Intensive osteoclast differentiation leads to the generation of more osteoclasts and increased bone resorption. This review provides insight into the impact of aging on bone, encompassing bone cell states during the aging process and bone signaling pathway transformations. It primarily delves into aging-related signaling pathways, such as the bone morphogenetic protein/Smad, Wnt/β-catenin, osteoprotegerin/receptor activator of NF-κB ligand/receptor activator of NF-κB, connexin43/miR21, and nuclear factor erythroid 2-related factor 2/antioxidant response element pathways, seeking to enhance our comprehension of crucial bone cells and their secretory phenotypes during aging. Furthermore, the precise molecular regulatory mechanisms underlying the interactions between bone signaling pathways and aging are investigated.

The immune responses following SARS-CoV-2 infection in children are still under investigation. While coronavirus disease 2019 (COVID-19) is usually mild in the paediatric population, some children develop severe clinical manifestations or multisystem inflammatory syndrome in children (MIS-C) after infection. MIS-C, typically emerging 2–6 weeks after SARS-CoV-2 exposure, is characterized by a hyperinflammatory response affecting multiple organs. This review aims to explore the complex landscape of immune dysregulation in MIS-C, focusing on innate, T cell-, and B cell-mediated immunity, and discusses the role of SARS-CoV-2 spike protein as a superantigen in MIS-C pathophysiology. Understanding these mechanisms is crucial for improving the management and outcomes for affected children.

Human microbiomes are microbial populations that form a symbiotic relationship with humans. There are up to 1000 species on the surface of human skin and mucosal system, among which gut microbiota attracts the most interest. As the beginning of the digestive tract, oral cavity is also an important microbial habitat in the human body which is the first line of defense against pathogens entering the body. Many studies have revealed that oral microbial dysbiosis could not only contribute to oral diseases but also whole-body systemic diseases and health status. Oral microorganisms can enter the gastrointestinal tract with saliva and food, or enter the blood circulation through mouth breakage, thus causing systemic inflammation and aging-related diseases including some causal links to Alzheimer’s disease. A series of changes take place in oral microbial composition during development, with different age stages marked by different dominant microbial species. Despite a lack of comprehensive studies on aging oral microbiota, through systemic inflammation, oral pathogenic microbes are likely to contribute inflammatory aging. As inflammaging is a key signature and one of the causes for accelerated aging, improving the structure of oral microbiome may be not only a new strategy for disease prevention and treatment, but also for aging intervention.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver condition, characterized by a spectrum that progresses from simple hepatic steatosis to nonalcoholic steatohepatitis, which may eventually lead to cirrhosis and hepatocellular carcinoma. The precise pathogenic mechanisms underlying NAFLD and its related metabolic disturbances remain elusive. Epigenetic modifications, which entail stable transcriptional changes without altering the DNA sequence, are increasingly recognized as pivotal. The principal forms of epigenetic modifications include DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. These alterations participate in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial injury, oxidative stress response, and release of inflammatory cytokines, all of which are associated with the onset and progression of NAFLD. This review discussed recent advances in understanding the potential epigenetic regulation of inflammation in NAFLD. Unraveling these epigenetic mechanisms may facilitate the identification of early diagnostic biomarkers and the development of targeted therapeutic strategies for NAFLD.