Cell Regeneration最新文献

Aging profoundly impacts bone homeostasis and regeneration, yet the cellular and molecular mechanisms underlying periosteal aging remain poorly understood. Using single-cell RNA sequencing, we profiled the periosteum of 3-, 9-, and 18-month-old mice, which revealed age-related shifts in progenitor, neutrophil, and macrophage subpopulations. Aging reduced mesenchymal cell populations and impaired osteogenic potential, may contribute to periosteal homeostasis. Periosteal progenitor subsets exhibited distinct aging trajectories: Dpt⁺ fibrous-layer cells undergoing early senescence, while Postn⁺ progenitors showed osteogenic decline. Aging also shifted immune profiles, increasing inflammatory Cd38^hi macrophages and dysfunctional Nlrp3^hi neutrophils, further disrupting bone homeostasis. Notably, aged progenitor cells upregulated CSF1 and CXCL signaling, driving macrophage and neutrophil infiltration, exacerbating bone loss. Our findings provide a comprehensive periosteal aging atlas, revealing aging-associated alterations in progenitor-immune crosstalk that may influence bone tissue dynamics, and offering insights into potential targets for age-related skeletal conditions.

Hypoxia-ischemia plays a role in the physiological and pathological processes of various diseases and presents a common challenge for humans under extreme environmental conditions. Neurons are particularly sensitive to hypoxia-ischemia, and prolonged exposure may lead to irreversible brain damage. The primary mechanisms underlying this damage include energy depletion, mitochondrial dysfunction, oxidative stress, inflammation, and apoptosis. Mitochondria serve as primary organelles for adenosine triphosphate (ATP) production, and mitochondrial dysfunction plays a crucial role in mediating hypoxic pathophysiological processes. Hypoxic-ischemic preconditioning (H/IPC) is an endogenous cellular protective mechanism that reduces the damage caused by lethal hypoxic stressors. In this review, we summarize the potential role of H/IPC and its protective effects on mitochondrial quality control and function. This perspective offers a new approach for treating diseases caused by hypoxia-ischemia.

Vertebrate axis patterning requires precise control of the differentiation of neuromesodermal progenitors (NMPs), which generate spinal cord (SC) and presomitic mesoderm (PSM). Previously, we identified a gastrula-premarked posterior enhancer (p-Enh) that is essential for posterior tissue development by regulating somite and SC in organogenetic embryos, while its role in early NMPs cells remains elusive. Here, using a highly efficient in vitro differentiation system, we found that the genetic removal of p-Enh leads to the aberrantly up-regulated PSM-related genes during both PSM and SC differentiation. Time-resolved transcriptomic analysis and experimental characterization revealed the activated PSM transcriptomic signature arose from disorganized NMPs composition, with an over-representation of the T^highSOX2^low NMPs subtype. Besides, through a newly developed bioinformatic tool, ST-Pheno, which effectively bridges the in vitro samples to in vivo embryonic phenotypes within spatiotemporal context, we determined that the over-produced T^highSOX2^low NMPs subtype is predominantly enriched in the anterior primitive streak and adjacent mesoderm region at E7.5, which may disrupt the proper development of NMPs towards prospective PSM and SC, ultimately leading to the posterior development failure. In summary, this study demonstrates a critical role of p-Enh in regulating NMPs subtype composition, which will broaden the molecular understanding of mammalian embryogenesis.

To adapt to gravitational forces during the transition to terrestrial life, animals evolved specialized paw skin to withstand their body weight and allow for locomotion. In a recent Cell article, Di et al. demonstrate SLURP1 as an endoplasmic reticulum (ER) membrane protein that protects palmoplantar keratinocytes from mechanical stress by preserving SERCA2b activity and inhibiting the pPERK-NRF2 signaling under mechanical pressure.

The adult mammalian heart lacks the capacity to regenerate after injury, leading to heart failure. While most of the research focused on the cardiomyocyte proliferation around the infarct zones, a new study (Fan et al., Cell Stem Cell 32(1563-1576):e1511, 2025) reveals a novel mechanism in the remote endocardial zone. They identified lysozyme 2 (Lyz2) as a critical regulator, where its sustained activity in the non-regenerative hearts promotes lysosomal degradation of the extracellular matrix (ECM). Then, the breakdown of ECM was found to induce cardiomyocyte apoptosis near the endocardium. Importantly, both the genetic deletion of Lyz2 or the pharmacological inhibition of lysosomal degradation activity in mice after myocardial infarction (MI) preserved the ECM, reduced cardiomyocyte apoptosis, diminished scarring, and improved cardiac function. This work highlights LYZ2 as a novel therapeutic target for promoting heart repair in humans.

Primary human hepatocytes (PHH) are used as the FDA-recognized "gold standard" for liver-related studies in vitro. The world's first PHH group standard (T/CSCB 0008-2021, CSCB standard) was released by Chinese Society for Cell Biology in 2021. In order to justify this standard, six key quality attributes of ten different batches from commercial PHHs, including cell viability, cell morphology, cell markers, albumin secretion, drug metabolism function and bile secretion, were characterized using the designated test methods in the standard. The PHHs from various batches all exhibited typical hepatocytic morphology, high cell viability, and sufficient albumin secretion; whereas, tremendous variations in cell markers, drug metabolism functions, and bile secretion were unexpectedly detected across the board. Flow cytometric assessment of hepatocyte markers revealed the percentages of ALB⁺ or HNF4A⁺cells in six batches of PHHs, ranging from 49.4% to 98.9% and from 37.7% to 91.4%, respectively. Single cell transcriptomic analysis also revealed significant cell heterogeneity across the different batches, with the proportions of hepatocytes ranging from 69.2% to 98.9%. Considerable heterogeneity in drug metabolism functions across the batches were also found in substrate clearance rate (SCR) and metabolite formation rate (MFR) for six representative CYP450 enzymes, while the results didn't influence current SCR attribute of CYP3A4. Metabolic capacity and purity are two independent attributes for PHH. The varied biliary excretion indexes around criteria (30%) indicated heterogeneity of PHH biliary excretion capacity. These results confirmed the robustness of most quality attributes in current CSCB standard, while highlighting the need to refine remaining parameters to enhance its practical applicability.

The adult mammalian heart exhibits minimal regenerative capacity due to postnatal cell-cycle arrest of cardiomyocytes. In contrast, lower vertebrates such as zebrafish retain the ability to fully regenerate heart after injury. This capacity is driven not only by transcriptional and structural plasticity but also by metabolic reprogramming that supports cardiomyocyte proliferation. Adult mammalian cardiomyocytes lack both features, remaining largely refractory to regenerative cues. These limitations have prompted efforts to identify extrinsic genetic and metabolic regulators capable of reactivating proliferative competence in adult cardiomyocytes. In this review, we highlight recent advances in the molecular and metabolic control of cardiomyocyte cell-cycle reentry, focusing on strategies that modulate dedifferentiation, proliferation, and redifferentiation as well as metabolic state transitions. We also examine emerging translational approaches in swine models, which more closely recapitulate human cardiac physiology than rodents. Together, these insights provide a roadmap for unlocking endogenous regenerative pathways and identify key challenges in translating these findings into therapies for heart failure.

Diabetes mellitus is a common and serious metabolic disease globally, characterized by increased blood glucose levels. The major pathogenesis is the functional impairment of insulin-producing beta cells in the pancreas and the lack of insulin secretion. Although both type 1 and type 2 diabetes develop through distinct pathological mechanisms, they lead to the destruction and/or dysfunction of beta cells, resulting in inadequate beta cell mass to maintain normal blood glucose levels. For this reason, therapeutic agents capable of inducing beta cell proliferation can be considered a possible approach to restore beta cell abundance and treat type 1 and type 2 diabetes. Although several methods have been found to promote the replication of beta cells in animal models or cell lines, it is still challenging to promote the effective proliferation of beta cells in humans. This review highlights the different agents and mechanisms that facilitate pancreatic beta cell regeneration. Numerous small molecules have been discovered to influence beta cell proliferation, primarily by targeting cellular pathways such as DYRK1A, adenosine kinase, SIK, and glucokinase. Additionally, receptors for TGF-β, EGF, insulin, glucagon, GLP-1, SGLT2 inhibitors, and prolactin play critical roles in this process. Stem cell-based clinical trials are also underway to assess the safety and efficacy of stem cell therapies for patients with type 1 and type 2 diabetes. We have emphasized alternative therapeutic pathways and related strategies that may be employed to promote the regeneration of pancreatic beta cells. The knowledge raised within this review may help to understand the potential drug-inducible targets for beta cell regeneration and pave the way for further investigations.

Neural regeneration stands at the forefront of neuroscience, aiming to repair and restore function to damaged neural tissues, particularly within the central nervous system (CNS), where regenerative capacity is inherently limited. However, recent breakthroughs in biotechnology, especially the revolutions in genetic engineering, materials science, multi-omics, and imaging, have promoted the development of neural regeneration. This review highlights the latest cutting-edge technologies driving progress in the field, including optogenetics, chemogenetics, three-dimensional (3D) culture models, gene editing, single-cell sequencing, and 3D imaging. Prospectively, the advancements in artificial intelligence (AI), high-throughput in vivo screening, and brain-computer interface (BCI) technologies promise to accelerate discoveries in neural regeneration further, paving the way for more precise, efficient, and personalized therapeutic strategies. The convergence of these multidisciplinary approaches holds immense potential for developing transformative treatments for neural injuries and neurological disorders, ultimately improving functional recovery.

Embryo models derived from pluripotent stem cells (PSCs) have become powerful tools for dissecting mammalian embryonic development and advancing regenerative medicine. Two recent studies in Cell and Cell Stem Cell report major advances in generating mouse embryo models that replicate development up to early organogenesis (equivalent to embryonic day 8.5~8.75). Li et al. describe a purely chemical strategy to reprogram mouse embryonic stem cells (mESCs) into induced embryo founder cells (iEFCs) capable of forming complete embryo models (iEFC-EMs). In parallel, Yilmaz et al. demonstrate transgene-free generation of post-gastrulation models (TF-SEMs) from naive mESCs and induced pluripotent stem cells (iPSCs) using a similar chemical cocktail. Both models faithfully recapitulate key developmental events, including gastrulation, neural tube formation, cardiogenesis, and somitogenesis. These advances not only deepen understanding of early mammalian development but also pave the way for applications in regenerative medicine and disease modeling.