Mesenchymal stem cells (MSCs) exhibit potent immunomodulatory properties, yet their precise mechanisms in alleviating Echinococcus multilocularis-induced hepatic inflammation and fibrosis in Alveolar Echinococcosis (AE) remain elusive. This study aimed to elucidate the immunoregulatory mechanisms underlying MSCs therapy in AE. Using an AE mouse model, we demonstrated that MSCs administration significantly ameliorated liver histopathology, attenuated fibrosis, and restored liver function. Molecular analyses revealed that AE infection promoted a pro-inflammatory profile (elevated RORγt and IFN-γ) while suppressing regulatory factors (FOXP3, TGF-β1, IL-10, CNTN1, and Gilz), effects that were robustly reversed by MSCs treatment. In vitro, co-culture of CNTN1-knockdown MSCs with E. multilocularis antigen-stimulated CD4[+] T cells demonstrated that CNTN1 deficiency impaired MSCs-mediated immunoregulation, decreased IL-10 secretion, and disrupted the Th17/Treg balance. Mechanistically, dual-luciferase reporter assays confirmed that CNTN1 directly activates the Gilz promoter. Collectively, our findings identify the CNTN1/Gilz signaling axis as an essential mediator of MSCs immunomodulation, providing novel mechanistic insights into the therapeutic efficacy of MSCs against E. multilocularis-induced hepatic injury.

Conventional therapies for endocrine hormone deficiencies, including hormone replacement therapy and solid organ transplantation, are hampered by the lack of physiological regulation or donor shortage, respectively. Directed differentiation of human pluripotent stem cells has opened new avenues for cell replacement therapy; however, research on different endocrine glands has long been conducted in isolation, with limited cross-disciplinary exchange of technical expertise. This Review takes the clinically most advanced stem cell-derived pancreatic β cells as a methodological reference and establishes a three-tier translational challenge model-cell identity, in vivo survival, and functional delivery-to systematically compare the regenerative progress and specific hurdles of thyroid, parathyroid, pituitary, and adrenal cells. We highlight transferable strategies emerging from these lineage-specific studies, including temporal developmental signaling modulation, modular lineage assembly, prevascularization engineering, and hierarchical immunocompatibility design. Through this cross-lineage comparative framework, this Review aims to break the isolated research paradigm and provide a methodological foundation for endocrine regenerative medicine to evolve from isolated efforts toward synergistic advancement.

Liver transplantation remains the only definitive therapy for end stage liver disease, yet its application is fundamentally constrained by donor organ scarcity. Despite advances in organ preservation, marginal graft utilization, and xenotransplantation, a scalable source of functional liver tissue has not been realized. Blastocyst complementation has emerged as a novel strategy to generate exogenic organs, enabling the development of human derived hepatocytes within a xenogeneic host. The approach introduces a distinct biological paradigm where human parenchymal cells coexist with partial xenogeneic non-parenchymal compartments, resulting in compartmentalized immunogenicity. Efficient human-porcine blastocyst complementation remains an evolving technology, and functional exogenic humanized livers have yet to be demonstrated in large-animal transplant models. We examine exogenic liver transplantation through an immunology-first, clinical framework with emphasis on early graft injury driven predominantly by innate immune mechanisms at the vascular interface, including complement activation, macrophage mediated clearance, thrombocytopenia, and coagulation dysregulation as a major barrier observed in liver xenotransplantation. While adaptive immune responses may be attenuated due to reduced antigenic burden, residual xenogeneic endothelial and stromal compartments remain critical drivers of immune activation. We highlight exogenic hepatocyte transplantation as a potential translational bridge, enabling functional validation of chimerism-derived human hepatocytes in vivo while bypassing the vascular incompatibility inherent to whole organ transplantation. This cell-based therapy could offer a platform before the clinical realization of whole exogenic liver transplantation. We propose a phased immunomodulatory approach centered on early control of innate and humoral injury using induction therapy, plasmapheresis, and complement modulation, followed by tolerance-oriented tapering of maintenance immunosuppression. Finally, we outline a translational pathway incorporating preclinical validation, ex vivo perfusion, and human decedent transplant models, while addressing ethical, biosafety, and logistical considerations. Exogenic liver transplantation has the potential to represent a transformative strategy to generate scalable, immunologically optimized grafts and redefine the future of liver transplantation.

Cell transplantation is a potential therapeutic strategy for ischemic stroke, but its clinical efficacy remains inconsistent. This meta-analysis evaluated functional outcomes at different follow-up time points, as well as neuroimaging and paracrine biomarkers. A systematic search of Embase, PubMed, Web of Science, and the Cochrane Library up to December 31, 2025 identified 21 randomized controlled trials involving 1,269 patients. The analysis showed that cell transplantation improved NIHSS at 6 and 12 months and final follow-up; mRS at 12 months and final follow-up; and BI at 3 and 6 months and final follow-up. Functional independence increased as measured by mRS scores at 0-1 and 0-2 at 12 months and by BI ≥90 or 95 at 3 and 12 months and final follow-up. MSCs improved NIHSS and BI, EPCs improved NIHSS and mRS, whereas MNCs showed no statistically significant effects. BBB-bypassing delivery demonstrated consistent efficacy. Transplantation within 10 days or after 90 days showed beneficial effects. Fugl-Meyer assessment scores and VEGF increased after cell transplantation, while infarct volume and DTI-FA showed no change. Cell transplantation induced functional benefits. Efficacy may depend on cell type, delivery strategy, and timing of transplantation, underscoring the critical influence of these variables on therapeutic outcomes.

Genetically engineered porcine red blood cells (pRBCs) are emerging as a potential supplementary source of oxygen-carrying cells for transfusion medicine. Triple-knockout (TKO) pigs lacking major carbohydrate xenoantigens, including Gal, Neu5Gc, and Sd(a), have substantially reduced human antibody binding in vitro, and additional expression of human protective molecules such as CD55 and CD47 may further improve compatibility. However, the translational development of pRBC xenotransfusion is now constrained less by donor engineering alone than by the absence of an appropriate in vivo evaluation model. Old World nonhuman primates have historically served as essential preclinical models in xenotransplantation, but their cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH)-positive background and natural antibody repertoires may exaggerate immune barriers to TKO pRBCs that are not fully representative of humans. New World nonhuman primates, brain-dead human models, and eventually carefully regulated early-phase human studies each offer distinct advantages and limitations. In this Commentary, we argue that pRBC xenotransfusion requires a purpose-specific translational framework rather than reliance on a single preclinical model. Such a framework should integrate standardized compatibility testing, in vitro human assays, animal-based safety stress-testing, and, where ethically and legally feasible, short-term human reference models.

Human herpesvirus 7 (HHV-7) encephalitis commonly occurs in immunocompromised individuals and has a poor prognosis. We here reported 3 cases of HHV-7 encephalitis following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with typical neurological symptoms, including altered consciousness and epileptic seizures, and conducted a systematic review of the literature to identify clinical characteristics and management strategies in these patients. Cerebrospinal fluid next-generation sequencing (NGS) was the key evidence that led to their diagnosis. Foscarnet and cidofovir appeared effective, particularly with at least four weeks of treatment. All three patients showed at least partial improvement in neurological symptoms. Furthermore, a systematic search was conducted in PubMed, Google Scholar, and Web of Science to identify related cases. Clinical presentation, diagnostic findings, treatment strategies, and outcomes were analyzed. A total of 10 publications were included, together with our 3 cases, comprising 7 cases of HSCT recipients for detailed analysis. Our study suggested that early recognition and prompt antiviral therapy are critical for improving prognosis. Further exploration is needed regarding risk factors and treatment strategies.

Donor-specific immunomodulatory cells (DSIMC) have successfully induced donor-specific tolerance in clinical living donor liver transplantation. These cells are generated from recipient peripheral blood mononuclear cells (PBMCs) stimulated with irradiated donor PBMC in the presence of costimulatory blockade, yielding a heterogeneous population of recipient-derived immune cells including T cells, B cells, and NK cells, in which CD4[+] regulatory T cells (Tregs) are thought to play a central role. Here, we examined the cell populations and functions crucial for donor-specific immunomodulation within the DSIMC product. DSIMC were generated from PBMC of healthy volunteers using belatacept to achieve costimulatory blockade. Tregs were enriched by CD4[+]CD25[+] magnetic-cell activated cell sorting (MACS) or CD25[+]CD127[-/low] fluorescence-activated cell sorting (FACS). CD4[+], CD8[+], CD19[+], and CD25[+]CD127[-/low] fractions were also individually depleted from DSIMC. Immunomodulatory function of each resulting population was assessed by tritium-labelled thymidine incorporation in mixed lymphocyte cultures (MLC), and cytokine-producing capacity was evaluated by ELISA/ELISpot assays. Unsorted DSIMC exhibited donor-specific suppression at lower cell numbers than CD4[+]CD25[+] enriched cells, while CD4[+]CD25[-] T cells showed no immunosuppressive effect. Depletion of CD4[+], CD8[+], or CD19[+] cells did not substantially impair immunomodulatory function. In contrast, depletion of the CD25[+]CD127[-/low] fraction reduced inhibitory function and abolished donor specificity. Depletion of CD4[+] or CD25[+]CD127[-/low] reduced IFN-γ and IL-10 production in response to donor stimulation compared with unsorted DSIMC, implicating CD4[+] Tregs as important contributors to cytokine production under allogeneic stimulation. Furthermore, Treg expansion following donor antigen restimulation was observed in unsorted DSIMC but not in CD4[+]CD25[+]-enriched cells, suggesting that Tregs can be induced from non-Treg CD4[+] populations within the DSIMC. In conclusion, CD4[+]CD25[+]CD127[-/low]FoxP3[+]-associated cells appear to contribute to donor-specific immunomodulation; however, the enrichment of CD4[+]CD25[+] T cell diminished DSIMC efficacy. Since the unsorted DSIMC showed stronger activity, we suggest that multiple cell populations may act together to mediate the DSIMC effect.

Bioengineered livers using decellularized extracellular matrix (ECM) scaffolds hold promise for transplantation therapies. However, conventional recellularization methods involving cell injection via blood vessels encounter challenges in recapitulating the complexity of hepatic tissues, including high cellularity, differentiation hierarchy, and cellular heterogeneity. Here, we developed a methodology termed "combined single-cell and organoid (CSO) injection." We injected human liver organoids (HLOs) and dispersed organoid cells via direct puncture and vascular injection into a decellularized porcine ECM scaffold, respectively. This process facilitated the construction of densely populated and self-organized liver-like tissues (CSO Livers) that formed cell-cell/cell-ECM interactions. The tissues displayed hepatic characteristics, including ALBUMIN secretion, robust expression of liver-associated genes, and cellular heterogeneity comprising hepatocytes, cholangiocytes, as well as stellate-like and endothelial cells. Furthermore, we demonstrated that CSO-Livers functioned as grafts in immunodeficient mice and in a microminipig model of liver fibrosis through transplantation via vascular anastomosis. These findings indicate the applicability of the combined single-cell and organoid (CSO) injection method for generating bioengineered liver grafts using HLOs.

Radiation-induced brain injury (RIBI) is a serious complication of cranial radiotherapy and currently lacks effective disease-modifying treatment. Persistent neuroinflammation and neurovascular dysfunction are considered central to RIBI progression, making them attractive therapeutic targets for regenerative intervention. Multilineage-differentiating stress-enduring (Muse) cells are a non-tumorigenic pluripotent-like cell population with reported reparative and immunomodulatory properties, but their therapeutic potential in RIBI has not been defined. In this study, we evaluated the effects of Muse cell transplantation in experimental RIBI using in vitro neurovascular co-culture systems and in an vivo rat model. Irradiation induced marked activation of inflammasome-related signaling, endothelial injury, and neurological impairment. Muse cells suppressed the expression of NLRP3, AIM2, ASC, Caspase-1, IL-1β, and IL-18 in irradiated co-culture systems, while preserving endothelial proliferative and angiogenic responses. Transcriptomic analysis identified stress-related pathways associated with Muse cell-mediated protection, and PPAN emerged as a candidate regulator linked to the reparative phenotype. In vivo, intracarotid transplantation of Muse cells reduced [18F] DPA-714 uptake in irradiated brain tissue and was accompanied by supportive behavioral trends suggestive of functional improvement. These findings provide exploratory preclinical evidence that Muse cell transplantation attenuates neuroinflammatory activation and preserves endothelial reparative responses after radiation-induced brain injury. Muse cells may therefore represent a potential cell-based strategy for RIBI, although their therapeutic efficacy, neurovascular repair-related effects, and long-term functional benefits require further validation in larger and more comprehensive preclinical studies.

Chronic and complex skin wounds, including diabetic ulcers and burns, represent a major clinical challenge with substantial morbidity and healthcare costs. Regenerative approaches have evolved from stem cell-based therapies toward stem cell-free strategies, particularly mesenchymal stroma/stem cell-derived extracellular vesicles (MSC-EVs). However, the relative strength, consistency, and translational readiness of these approaches remain unclear. The aim of this study is to synthesize and critically appraise evidence from systematic reviews and meta-analyses on cell-based and cell-free regenerative therapies for wound healing, with emphasis on clinical relevance, methodological quality, and recent developments. An umbrella review was conducted in accordance with PRISMA 2020 guidance. PubMed/MEDLINE, Scopus, and Web of Science were searched for systematic reviews and meta-analyses published in English within the last 5 years. Eligible reviews evaluated cell-based therapies and/or extracellular vesicle-based interventions for skin wound healing in clinical and/or animal models. Methodological quality was assessed using AMSTAR-2, and overlap of primary studies was evaluated using the corrected covered area (CCA). Seven systematic reviews and meta-analyses were included, encompassing both clinical and preclinical evidence. Notably, the majority of included evidence was derived from diabetic wound models, particularly in preclinical animal studies. Cell-based therapies demonstrated clinically relevant benefits in specific settings, such as autologous skin cell suspensions for burns and biologic skin substitutes for diabetic foot ulcers, although certainty of evidence was low to moderate. In contrast, MSC-EVs showed large and consistent effects on wound closure, angiogenesis, collagen deposition, and inflammatory modulation in preclinical models. No randomized human trials of EV-based wound therapies were identified. Current evidence suggests a paradigm shift toward stem cell-free regenerative strategies in wound healing. While cell therapies have limited but established clinical roles, MSC-EVs offer strong preclinical efficacy and translational potential. Standardization, regulatory alignment, and well-designed clinical trials are required to enable safe clinical implementation.

Chronic graft-versus-host disease (cGVHD) remains the leading cause of late non-relapse mortality and long-term disability after allogeneic hematopoietic cell transplantation (allo-HCT), affecting 30-70% of long-term survivors. Despite its substantial morbidity and the toxicities associated with prolonged corticosteroid use, therapeutic advances have accelerated considerably. This review synthesizes current mechanistic insights and clinical evidence within the framework of the well-established three-phase pathogenesis model of cGVHD. Phase 1 (early inflammation) involves tissue injury and innate immune activation; Phase 2 (months 2-12) is characterized by impaired central and peripheral tolerance with aberrant B- and T-cell responses; Phase 3 (>1 year) features macrophage-driven fibrosis and end-organ damage. Recognizing that these phases are conceptual and frequently overlap in clinical practice, we explore the alignment of contemporary biomarkers with each phase-ST2/CXCL9 (Phase 1), BAFF/autoantibodies (Phase 2), and MMP3/TGF-β (Phase 3)-and discuss how FDA-approved agents (ibrutinib, ruxolitinib, belumosudil, axatilimab) may target phase-specific pathways. A conceptual, risk-stratified treatment algorithm is proposed to link pathobiology to clinical decision-making, with the important caveat that biomarker-guided selection remains investigational and currently complements, rather than replaces, comprehensive clinical assessment. Notably, the adoption of prophylaxis and upfront strategies to prevent cGVHD has substantially reduced cGVHD incidence in modern cohorts.

Islet transplantation is a promising treatment for diabetes, but the shortage of donor islets limits its broad application. Induced pluripotent stem cells (iPSCs) provide an alternative source for generating insulin-producing cells; however, whether the somatic cell origin of human iPSCs influences pancreatic endocrine differentiation remains incompletely defined. In this study, we generated iPSCs from human pancreatic duct cells (HD-iPSCs) and compared their differentiation propensity and functional characteristics with human fibroblast-derived iPSCs (HF-iPSCs) under identical differentiation conditions. HD-iPSC-derived cells showed higher expression of pancreatic endocrine and β-cell-associated markers, including insulin, PDX1, and FOXA2, compared with HF-iPSC-derived cells. Flow cytometric analysis further confirmed a higher proportion of insulin-positive cells in differentiated HD-iPSC-derived cells. Functionally, HD-iPSC-derived cells exhibited greater glucose-stimulated C-peptide secretion than HF-iPSC-derived cells, although their secretory capacity remained lower than that of native human islets. Following transplantation into streptozotocin-induced diabetic mice, HD-iPSC-derived cells reduced blood glucose levels more effectively than HF-iPSC-derived cells, and insulin-positive grafts were detected in vivo. These findings suggest that human pancreatic duct cell-derived iPSCs have enhanced pancreatic endocrine differentiation potential compared with fibroblast-derived iPSCs. Although further maturation and optimization are required, pancreatic duct cells may represent a favorable somatic cell source for generating iPSC-derived insulin-producing cells for diabetes cell therapy.

Stromal vascular fraction (SVF)-based therapies and autologous fat grafting have emerged as promising regenerative strategies due to their pro-angiogenic, immunomodulatory, and trophic properties. However, despite encouraging preclinical and clinical findings, therapeutic outcomes remain highly heterogeneous, with marked variability in graft retention and functional efficacy between patients. Increasing evidence suggests that this variability cannot be explained solely by procedural factors or cellular composition, but may also depend on host-related immune and microenvironmental determinants. This review explores the biological mechanisms governing SVF engraftment and introduces the emerging concept of "SVF therapy resistance," defined as the failure of autologous regenerative therapies resulting from maladaptive interactions between transplanted stromal cells and the host tissue environment. Particular attention is given to sterile inflammation, innate immune activation, and early graft-host interactions. Following transplantation, tissue injury and ischemia induce the release of danger-associated molecular patterns (DAMPs), triggering neutrophil recruitment, macrophage activation, complement signaling, and inflammatory remodeling. While controlled inflammatory responses may support tissue repair and angiogenesis, excessive neutrophil activation, neutrophil extracellular trap (NET) formation, persistent pro-inflammatory macrophage polarization, and impaired vascular adaptation may compromise graft survival and regenerative efficacy. The review further discusses how SVF processing, inflammatory priming, stromal cell heterogeneity, and donor-related factors-including obesity, aging, metabolic dysfunction, and chronic inflammation-may influence therapeutic responsiveness. Emerging evidence from mesenchymal stromal cell biology suggests that stromal cells are highly sensitive to inflammatory licensing and microenvironmental cues. Candidate biomarkers and immune profiling strategies capable of identifying responders and non-responders to SVF-based therapies are also reviewed. Finally, these mechanisms are discussed in spinal cord injury, a condition characterized by chronic inflammation and vascular dysfunction. Overall, this review proposes a translational framework linking innate immunity, sterile inflammation, angiogenesis, and stromal cell heterogeneity to the variability of SVF therapy outcomes, highlighting the need for personalized regenerative medicine approaches.

To investigate the efficacy and safety of MTBF as conditioning regimen for salvage allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with relapsed or refractory acute myeloid leukemia (R/R AML). We conducted a single-arm prospective clinical trial (NCT06385808). The main outcome was cumulative incidence of relapse (CIR), and the secondary outcomes were progression-free survival (PFS), overall survival (OS), engraftment time, graft-versus-host disease (GVHD), and non-hematological adverse effects. Twenty-four R/R AML patients from the First Affiliated Hospital of Xi'an Jiaotong University were enrolled, and all achieved engraftment. Mucositis was the predominant toxicity and was managed appropriately. The two-year CIR was 10%. The two-year OS and PFS were 78.9 ± 11.1% and 51.2 ± 19.3%, respectively. Two patients experienced relapse, and three patients died of infection. Subgroup analyses demonstrated that maintenance treatment post-transplantation may improve OS. The MTBF regimen for salvage allo-HSCT in R/R AML exhibited notable anti-leukemia activity and tolerable toxicity. (NCT06385808, Efficacy and Safety of MTBF Conditioning Regimen for Salvageable Allo-HSCT in the Treatment of R/R AML).