Mesenchymal stem cells (MSCs) are a cornerstone of regenerative medicine, primarily due to their ability to secrete bioactive factors that modulate inflammation, promote tissue repair, and support regeneration. Recent research highlights the importance of preserving the native cellular microenvironment to optimize MSC function and survival post-transplantation. Preconditioning strategies, such as hypoxia exposure, have emerged as powerful tools to enhance MSC therapeutic potential by mimicking physiological conditions in their natural niche. This perspective article explores the metabolic adaptations induced by hypoxia in MSCs, focusing on shifts in mitochondrial function, glycolysis, oxidative phosphorylation, and metabolic intermediates that enhance cellular survival and bioactivity. We also discuss how these metabolic changes influence the composition and function of MSC-derived secreted factors, particularly exosomes and other extracellular vesicles, in modulating tissue repair. Furthermore, we provide an overview of preclinical and clinical studies that have evaluated hypoxia-preconditioned MSCs and their byproducts, assessing their efficacy in various therapeutic contexts. Special attention is given to the role of hypoxia-induced mitochondrial adaptations in improving MSC function and the emerging potential of metabolic inhibitors or respiration modulators as strategies to further refine MSC-based therapies. By integrating metabolic insights with clinical evidence, we aim to offer a comprehensive perspective on optimizing MSC culture conditions to enhance their regenerative properties, acknowledging that this remains a theoretical standpoint, as conventional culture methods are generally not conducted under hypoxic conditions. This approach holds promise for the development of more effective therapeutic strategies that leverage metabolic modulation to improve MSC-based interventions for a range of diseases.

The role of transcription factor Krüppel-like factor 4 (KLF4) in the modulation of myeloid cells is well known. KLF4 is involved in the differentiation and polarization of monocytes and macrophages as part of the immune response after infection, in wound healing, and in cancer. In addition, KLF4 is essential in stem cell reprogramming and the phenomenon of trained immunity - a form of innate immune memory marked by epigenetic and metabolic reprogramming. A novel and underexplored dimension of KLF4 biology lies in its alternative splicing (AS), which generates distinct isoforms that may drive the transcription factor's functions, depending on specific cellular environments, disease states, or signaling programs. This review presents current knowledge of KLF4 splicing in myeloid cells and explores novel connections for how KLF4 isoform diversity may contribute to cellular plasticity and differential immune responses of myeloid cells across physiological and pathological conditions.

Acquired aplastic anemia (AA) is a bone marrow failure syndrome characterized by pancytopenia and decreased hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, it can be either congenital or acquired, predominantly affecting adolescents and the elderly, with higher incidence in Asia compared to Europe and America. Current treatment options include allogeneic hematopoietic stem cell transplantation or immunosuppressive agents, yet proximately a third of patients fail to reach long-term survival. AA is primarily driven by immune-mediated destruction of HSPCs, initiated by self-activated T cells. Early stages feature a Th1 response, which later shifts to Th17 and effector memory CD8+ T cells. Key cytokines including interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) play crucial roles in this immune dysregulation, influencing HSPCs and contributing to bone marrow failure. Furthermore, bone marrow macrophages (MΦ), particularly M1 subtype, are implicated in AA via the TNF-α/TNF-α receptor pathway, leading to T cell activating and subsequent HSPC damage. Interestingly, MΦ with high expression of IL-27Ra have been demonstrated to contribute to HSPC destruction in AA murine models. Beyond their role in thrombosis, platelets also participate in immune regulation. Some studies suggest that platelet may modulate T cell responses through mechanisms such as Akt-PGC1α-TFAM pathway or PF4-mediated activity, which could play a role in AA. However, direct evidence connecting platelet regulation to T cell-mediated HSPC damage is limited, and current research has largely focuses on CD8+ T cells. Moving forward, it is essential to investigate the interactions between platelets, CD4+ T cells, and mitochondrial energy metabolism. In this review, we propose that platelet-derived factors such as PF4 and TGFβ may activate mitochondrial pathways, influencing T cell activation and leading to HSPC destruction in AA. This hypothesis could provide new insights into the molecular mechanisms of AA and pave the way for novel therapeutic strategies (Highlight).

Atopic dermatitis (AD) is a chronic inflammatory disease characterized by severe itching and eczematous lesions. Despite various treatments, AD patients experience side effects and fail to achieve full remission. This study investigated the therapeutic potential of extracellular vesicles (EVs) derived from IFN-γ-primed induced mesenchymal stem cells (IFN-γ-iMSC-EVs) in a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model. We also examined whether IFN-γ-iMSC-EVs could suppress IL-4/13-induced Th2 responses in keratinocytes. The therapeutic outcome of IFN-γ-iMSC-EVs was comparable to or more effective than baricitinib or clobetasol. While severe weight loss was observed in mice treated with clobetasol, no significant weight reduction occurred in those receiving IFN-γ-iMSC-EVs. Histological analysis demonstrated reduced skin thickness, decreased infiltration of mast cells and inflammatory cells, and suppression of the Th2 immune response, as evidenced by decreased signalling of IL-4, IL-13, and IL-31. IFN-γ-iMSC-EVs also led to a greater reduction in inflammation and pruritus compared to baricitinib and clobetasol. Additionally, skin barrier integrity and epidermal protein expression were improved in IFN-γ-iMSC-EVs. In IL-4/13-stimulated keratinocytes, the decrease in JAK1/2 gene expression and the increase in Keratin 1 gene expression were more prominent in IFN-γ-iMSC-EVs than in baricitinib. The results suggest that IFN-γ-iMSC-EVs have the potential to inhibit AD progression and represent a novel therapeutic option for AD.

Psoriasis is a common chronic inflammatory skin disease. Acupoint injection is reported to be used for the treatment of psoriasis, however its mechanism is not yet clear. The study aimed to investigate the efficiency of combined treatment including acupoint injection in the treatment of psoriasis.

Stem cells have recently gained prominence in regenerative medicine, particularly in the treatment of neurological disorders. As a result, Human-induced Pluripotent Stem Cells (hiPSCs) have become a significant focus.

Over 20 years of research on human pluripotent stem cell (hPSC)-based therapies for Parkinson's disease (PD) has recently culminated in clinical trials. The first clinical report on autologous transplantation of patient-derived hPSCs showed significant motor symptom improvement, validating the therapeutic promise of this approach. However, critical challenges remain, notably the limited engraftment and survival of donor cells. Cellular stress incurred during in vitro differentiation of hPSCs into midbrain dopaminergic progenitors and neurons contributes to the reduced survival of grafted mDA neurons. Additionally, the host brain environment at the injection sites becomes hostile to transplanted cells due to needle trauma, immune rejection, and alpha-synuclein pathology present in the brains of PD patients. This review discusses potential strategies to address both intrinsic donor cell stress and hostile host brain environment, aiming to enhance the long-term efficacy and engraftment of hPSC-based cell therapies for PD.

OXA1L is crucial for mitochondrial protein insertion and assembly into the inner mitochondrial membrane, and its variants have been recently linked to mitochondrial encephalopathy. However, the definitive pathogenic link between OXA1L variants and mitochondrial diseases as well as the underlying pathogenesis remains elusive.

The Endothelial Activation and Stress Index (EASIX) has emerged as a significant prognostic indicator in various hematological malignancies. However, its role as a predictive biomarker in T-Cell Lymphoma remains unestablished. The purpose of this study is to assess the clinical relevance of EASIX in predicting Overall Survival (OS) and Progression-Free Survival (PFS) among T-cell lymphomas patients.

Doxorubicin (DOX), an anthracycline-based anticancer drug, is commonly used to treat various cancers, but its prolonged use may lead to cardiotoxicity. Despite extensive research efforts, effective strategies for managing DOX-induced cardiotoxicity (DICT) remain limited. This study investigated the DICT-inhibitory efficacy of the water extract of Allium victorialis L. (AVE) and its underlying mechanism. AVE protected mouse cardiomyocytes, H9c2 cells, from DOX-induced toxicity while not interfering with DOX's cytotoxic effect on the MDA-MB-231 cells, human breast cancer cells. DOX-induced abnormal heart rate, RR interval, cQT prolongation, and segmentation were normalized following AVE supplementation. Also, AVE reduced the serum levels of creatine kinase and lactate dehydrogenase and suppressed myocardial fibrosis and cell death by DICT in the AVE-fed mice group. Moreover, AVE was shown to restore DOX-induced impaired electrophysiological changes in human-induced pluripotent stem cell-derived cardiomyocytes, including reduced total activity and decreased conduction velocity, while also normalizing the beat period irregularity and beat period mean. A total of 57 metabolites were tentatively identified in the AVE sample. Furthermore, PCR microarray and western blot analyses confirmed that AVE reversibly increased the expression of antioxidant-related genes and proteins. Altogether, the antioxidant properties of AVE could be utilized as a new strategy for preventing and treating DICT.

Peripheral nerve injuries lead to significant motor deficits, with limited treatment options for full functional recovery. Distal electrical stimulation (E-stim) has shown promise in promoting neuromuscular reinnervation, though its mechanisms are not yet fully understood. This study aims to investigate the regulatory effects of distal E-stim on neuromuscular junction (NMJ) reinnervation and Satellite cell activity in denervated muscle injury.

Exosomes, containing molecular constituents of their cell of origin, including proteins and nucleic acids, were first discovered in immature red blood cells in 1983. Excellent intercell communication can be achieved by shuttling these various molecules between cells. Stem cell-derived exosomes (SC-Exos) contain paracrine-soluble factors that play important roles in tissue development, homeostasis, and regeneration. This paracrine activity of SC-Exos has been found to be a predominant mechanism by which stem cell-based therapies mediate their effects on degenerative, autoimmune and/or inflammatory diseases. Compared to other types of stem cells, human embryonic stem cells (hESCs), human induced pluripotent stem cells (hiPSCs), human mesenchymal stem cells (hMSCs) are the most popular because of their efficient immunomodulatory effects. The advantages and disadvantages of using exosomes isolated from the stem cell trio for therapeutic applications are further discussed in this review.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious complication associated with bisphosphonate (BP) therapy. Enhancement of the osteogenic differentiation of human jaw bone marrow mesenchymal stem cells (JBMMSCs) is a key issue in the treatment of BRONJ. In this study, we investigated the role and mechanism of LINC01013 in regulating osteogenic differentiation of JBMMSCs.

Increased production of the modern dairy cow can induce a stress response by the mammary epithelial cells (MEC) and compromise production traits. To alleviate this stress response, various strategies have been tested. Previous studies have shown an immunomodulatory effect of mesenchymal stem cells (MSC) and their secretome on different cell types and tissues; however, their effect in the context of lactation performance has not yet been studied. In this study, we aimed to assess the effects of MSC and their secretome on the stress response and lipogenesis in bovine MEC.

Fat grafting has been extensively used in plastic surgery practice, yet unstable retention in the recipient site remains a significant clinical challenge. The limited tolerance of injected adipose tissue to ischemia has prompted strategies aiming at timely enhancing the vascularity of the grafted fat. Various modified fat graft preparations have been used, and the mechanically processed tissue stromal vascular fraction (tSVF) derived from fat tissue has garnered considerable interest for enhancing rate of fat graft retention. Further enhancement of the graft retention and quality through supplements to tSVF is worthy of investigation.

The generation of organs derived from pluripotent stem cells can be achieved in vivo through the blastocyst complementation technique. This method is based on the introduction of pluripotent stem cells into organogenesis-disabled pre-implantation embryos, where environmental signals instruct donor cells to colonize the vacant niche and to develop into the missing organ. When applied interspecies, this approach has the potential to produce human organs in genetically engineered livestock, offering a promising solution to the global transplants' shortage crisis. In this review, we summarize the current progress in blastocyst complementation research and highlight the key challenges that must be addressed to advance this field.

Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy, primarily comprising intrahepatic (iCCA) and extrahepatic (eCCA) subtypes. Reconciling the variability between iCCAs and eCCAs in clinical trials remains a challenge, largely due to the inadequate understanding of their shared and subtype-specific cellular heterogeneity. We aim to address this issue using single-cell and spatially resolved transcriptomic approaches.

CX3CR1+ cells generate tissue macrophages in the developing heart and play cardioprotective roles in response to ischemic injuries in the adult heart. However, the origin and fate of CX3CR1+ cells during cardiogenesis remain unclear. Here, we performed genetic lineage tracing of CX3CR1+ cells and their progeny (termed Cx3cr1 lineage cells) in the mouse and demonstrated that they emerge from a subset of epiblast cells at embryonic day E6.5 and contribute to the parietal endoderm cells at E7.0. At E8.0-9.5 of development, Cx3cr1 lineage cells produced cardiomyocytes and endothelial cells via both de novo differentiation and fusion with pre-existing cardiomyocytes or endothelial cells, respectively. Cx3cr1 lineage cells persisted in the adult heart, comprising ~13% of cardiomyocytes and ~31% of endothelial cells. Additionally, CX3CR1+ cells differentiated from mouse embryonic stem cells generated cardiomyocytes, endothelial cells, and macrophages in vitro, ex vivo, and in vivo. Single-cell RNA sequencing revealed that Cx3cr1+ cells represent an intermediate cell population transitioning from embryonic stem cells to mesoderm. Taken together, embryonic CX3CR1+ cells constitute a multipotent epiblast-derived progenitor population that contributes not only to the formation of macrophages, but also of cardiomyocytes and endothelial cells.

Acute myeloid leukemia (AML), a heterogeneous and aggressive hematologic malignancy, remains challenging to treat due to high relapse rates, chemotherapy resistance, and the immunosuppressive tumor microenvironment (TME). While traditional therapies like chemotherapy and hematopoietic stem cell transplantation have improved outcomes, their efficacy is often limited by toxicity and disease recurrence. Recent advancements in antibody engineering have revolutionized AML immunotherapy, offering precision-targeted strategies to overcome these barriers. This narrative review explores the transformative role of monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and bispecific antibodies (bsAbs) in redirecting immune effector cells, blocking immune checkpoints, and eradicating leukemic stem cells (LSCs). Key innovations include CD33-targeted gemtuzumab ozogamicin, CD123-directed bispecific engagers, and anti-CD47 agents that disrupt "don't eat me" signals. We highlight breakthroughs in antibody design-such as Fc optimization, trispecific constructs, and conditionally active biologics-that enhance specificity while minimizing on-target off-tumor toxicity. Clinical trials demonstrate promising results, including improved remission rates and survival in refractory/relapsed AML when combining antibodies with hypomethylating agents, venetoclax, or checkpoint inhibitors. However, challenges persist, including AML's genetic heterogeneity, adaptive immune evasion, and cytokine release syndrome (CRS) risks. Emerging strategies such as biomarker-driven personalization, TME modulation, and engineered NK-cell engagers are poised to address these limitations. By integrating preclinical insights with clinical data, this review underscores the potential of antibody-based combinatorial regimens to redefine AML therapy, offering durable responses and bridging the gap to curative approaches.

Prostate epithelium develops from multipotent stem cells, which are replaced in adult life by different lineage-restricted basal and luminal unipotent stem cells. Deletion of Pten re-induces multipotency in basal cells (BCs); however, the molecular mechanisms regulating BC plasticity and tumor initiation are poorly understood. Here we showed that Pten deletion in BCs led to distinct cell fate reprogramming and tumor initiation in a regionalized manner. Single-cell RNA sequencing, ATAC-seq and in situ characterization revealed that following Pten deletion in anterior and dorsolateral prostates, BCs were highly plastic and reprogrammed into a hillock-like state, progressing into a proximal-like luminal state before giving rise to invasive tumors. This BC reprogramming was associated with the activation of innate immunity. Pharmacological targeting of interleukin-1, JAK-STAT and NF-κB as well as genetic deletion of Nfkb inhibit Pten-induced cell plasticity and reprogramming in a cellular autonomous manner, opening new opportunities for prevention and treatment of prostate cancer.