Tuberculosis (TB) remains a major global public health challenge, with drug-resistant tuberculosis (DR-TB) presenting a serious threat to TB management. Conventional treatment faces challenges such as significant drug toxicity, frequent emergence of drug resistance, and compromised host immune microenvironment. These limitations, particularly in DR-TB cases, often lead to poor treatment outcomes and heightened recurrence rates, underscoring the need for complementary strategies. Cell-based host-directed therapy (HDT) emerges as a novel therapeutic strategy that may complement conventional drugs by directly modulating pathological immune responses and facilitating the repair of damaged tissue. This narrative review synthesizes preclinical and clinical data on cell therapy for TB. We focus on two distinct strategic approaches: (1) mesenchymal stem cell (MSC)-based therapies, which primarily exert immunomodulatory and tissue-repair functions, and (2) T cell-based adoptive cell therapies (ACTs), which are designed to enhance antimicrobial immunity directly. Current evidence, while promising, predominantly remains in the early exploratory stages or lacks robust evidence-based support. To facilitate successful translation, future research should focus on standardizing cell products, conducting comprehensive safety assessments and implementing more rigorous clinical trials. This review critically assesses the therapeutic potential and translational challenges of cell therapy for TB.

Circadian rhythms are endogenous, transcription-translation feedback loops that align cellular activities with the 24-h light-dark cycle. Stem-cell populations across tissues exhibit circadian oscillations that influence their self-renewal, proliferation, and differentiation. Key developmental pathways (Wnt/β-catenin, Notch, and Hedgehog) are increasingly recognized as both regulators and targets of circadian machinery.

Acute liver failure (ALF) is a life-threatening syndrome characterized by rapid deterioration of liver function, resulting in high mortality and posing a substantial global health burden. Human embryonic stem cells (hESCs) possess unlimited self-renewal capacity and pluripotent differentiation potential. Transplantation of hESC-derived hepatocyte-like cells (HPLCs) represents a promising therapeutic strategy for ALF.

Craniofacial bone regeneration remains a major clinical challenge, yet the identity of orofacial mesenchymal stem/stromal cells (OMSCs) has not been fully elucidated. Here, we performed single-cell RNA sequencing (scRNA-seq) on mouse orofacial bone and identified multiple stromal cell clusters. Cell-cell communication mapping and trajectory inference uncovered the heterogeneity of OMSCs and functional divergence among subpopulations. We identified a previously unrecognized population, Smmhc-expressing mesenchymal stem/stromal cells (MSCs), at the earliest stage of the progenitor lineage trajectory. In vivo lineage tracing demonstrated that Smmhc+ MSCs are multipotent, giving rise to osteoblasts, osteocytes, periodontal ligament (PDL) cells, and dental pulp cells. Targeted ablation of Smmhc+ MSCs using SmmhcCreER;iDTR mouse model led to impaired orofacial bone development and disrupted orofacial tissue homeostasis, characterized by reduced osteogenic differentiation and non-cell autonomous reduction of bone resorption. Collectively, this study establishes a cellular atlas of OMSCs and identifies Smmhc+ MSCs as a functionally indispensable subset for craniofacial bone homeostasis, orchestrating the dynamic balance between osteogenesis and bone resorption within the orofacial skeletal niche.

Surrogate reproduction offers a promising biotechnological approach for accelerating aquaculture breeding. Grass carp (Ctenopharyngodon idellus), a key freshwater species, faces significant constraints in breeding due to its prolonged sexual maturation of 5 years and huge body size. Here, we establish an ultra-fast breeding strategy to generate all-female grass carp within six months via surrogate production in tiny laboratory fish, zebrafish (Danio rerio). We identify and isolate female GSCs from juvenile ovaries of 3-month-old grass carp. Three months after transplantation into zebrafish larvae, the donor-derived female GSCs undergo ultra-fast spermatogenesis and differentiate into functional grass carp sperm carrying X chromosomes. Fertilization of wild-type grass carp eggs with this sperm yields all-female offspring. This work demonstrates that fish female GSCs with XX chromosomes can differentiate into functional sperm in a short time in zebrafish gonadal somatic niche, opening a new avenue for precision breeding and sex control in aquaculture species.

Deficiency of adenosine deaminase 2 (DADA2) causes a complex phenotype of autoinflammation and immunodeficiency. Bone marrow failure is often refractory to treatment with tumour necrosis factor-alpha (TNF-alpha) inhibitors and additional treatment options are needed. However, the pathomechanisms underlying the disease remain incompletely understood. The aim of this study was to examine the viability and metabolic profile of ADA2-deficient cells and to characterise the activity of different cell death pathways to advance the mechanistic understanding of DADA2. By flow cytometry and western blot, we showed that ADA2-/- U-937 cells and PBMCs from DADA2 patients showed significantly elevated levels of cell death compared with cells expressing wild-type ADA2. Viability of ADA2-deficient cells was not improved by inhibitors of apoptosis, necroptosis, pyroptosis and ferroptosis. Blocking of TNF-alpha, type I interferon and STING signalling as well as reintroduction of wild-type ADA2 protein did not rescue the cell death phenotype in vitro. ADA2-deficient cells had an aberrant morphology with increased cell size and granularity and were impaired in their proliferative capacity. To identify the cause of the impaired viability, we performed 13C glucose tracer metabolomics experiments which revealed disturbances in the pentose phosphate pathway of ADA2-deficient cells. This tended to be associated with increased exposure to intracellular reactive oxygen species that was attenuated in the PBMCs of a DADA2 patient measured after successful hematopoietic stem cell transplantation. Collectively, our findings established increased levels of cell death as a possible pathomechanism of DADA2 and showed that the absence of ADA2 leads to an impairment of the pentose phosphate pathway which may account for the cellular vulnerability of ADA2-deficient cells.

Systemic sclerosis (SSc) is an autoimmune disease that transitions from vasculopathy as an initiating pathogenic event to tissue fibrosis. The mechanisms of these transitions remain, however, poorly understood, mainly because complex multicellular human models of SSc vasculopathy are lacking. We aimed to develop a complex multicellular human model of SSc vasculopathy and use it to investigate the mechanisms underlying this process.

Bone marrow contains abundant free fatty acids (FFA). Abnormal accumulation of FFAs can be triggered by pathological or physiologic conditions such as hyperlipidemia, diabetes mellitus, and menopause, leading to osteoporosis. Excess FFAs impair bone homeostasis by promoting osteoclast-mediated bone resorption and inhibiting the proliferation and differentiation of osteoblasts. C-type lectin domain family 11 member A (Clec11a) is an osteogenic growth factor that can protect islet proliferation and function against lipotoxicity. However, there is a lack of research on the function of Clec11a under bone marrow lipotoxic conditions. Here, we demonstrate that Clec11a counteracts the lipotoxicity-induced osteogenic inhibition and facilitates the proliferation and differentiation of osteoblasts. Clec11a effectively reverses palmitic acid(PA)-induced suppression of osteoblast proliferation and osteogenic differentiation, alleviates oxidative stress, and maintains mitochondrial homeostasis. Mechanistically, these protective effects of Clec11a depend on the SIRT3-SOD2 signaling axis, as the SIRT3 inhibitor 3-TYP abolishes its effects in both MC3T3-E1 cells and mouse bone marrow mesenchymal stem cells. Collectively, our findings reveal that Clec11a protects osteoblasts from PA-induced damage through regulation of the SIRT3-SOD2 signaling axis, providing mechanistic insights into bone impairment under lipotoxic conditions.

Chronic diabetic ulcers present a persistent challenge due to delayed wound healing. At the wound site, oxidative stress impairs stem cell survival and differentiation, accelerates senescence, and impairs autophagy. RLIM was identified as a critical regulator in human umbilical cord mesenchymal stem cells (hUCMSCs), where oxidative stress-induced RLIM upregulation leads to MDM2 degradation and stabilization of p53. Functionally, RLIM upregulation under oxidative stress inhibited autophagy, induced cellular senescence, and significantly impaired angiogenesis, cell migration, and immunomodulatory functions, ultimately hindering diabetic wound healing in vivo. These results highlight the RLIM-MDM2-p53 signaling axis as a pivotal pathway governing stem cell senescence and function under oxidative stress, offering promising therapeutic targets to enhance stem cell-based approaches for diabetic wound repair.

Owing to their highly porous architecture, cryogels have emerged as promising scaffolds for biomedical applications, particularly in the field of bone tissue engineering. However, their inherent mechanical fragility and biological inertness significantly constrain their broader applications. In this study, we developed a mineralized, dual-crosslinked cryogel based on ultra-high molecular weight polyethylene (UHMWPE) through sequential surface modifications strategy. This approach involved: (i) grafting of polydopamine (PDA) to introduce reactive groups; (ii) photocrosslinking of methacrylated gelatin (GelMA); (iii) conjugation of hyaluronic acid (HA); and (iv) deposition of a hydroxyapatite (HAp) layer via incubation in simulated body fluid (SBF). Collectively, these modifications substantially enhanced both the mechanical robustness and bioactivity of the cryogel. The engineered cryogels exhibited a 34.8-fold increase in compressive modulus (reaching 4.5 MPa) compared to the unmodified controls, along with markedly reduced water contact angles, demonstrating significantly improved mechanical strength and surface hydrophilicity. In vitro assessments further confirmed enhanced cellular responses, including promoted adhesion, migration, and osteogenic differentiation of rabbit bone marrow mesenchymal stem cells (rBMSCs) without exogenous inductive factors. This multi-scale modification approach presents an innovative paradigm for the design of high-performance scaffolds for bone tissue engineering.

The African spiny mouse (Acomys dimidiatus) is a unique mammalian model capable of scarless tissue regeneration, extending to the nervous system. Unlike conventional rodents, Acomys show significantly higher levels of adult brain stem cells, enhanced functional plasticity after brain injury, and the ability to regenerate and regain function following severe spinal cord damage. While the regenerative capacity of the Acomys central nervous system (CNS) is only beginning to be explored, existing studies have already challenged the long-standing dogma that adult mammals are incapable of CNS recovery after injury. This review provides a critical overview on the current knowledge of Acomys nervous system biology, from development to repair. We summarize the known cellular and mechanistic insights and highlight the current outstanding questions and research priorities. Understanding how Acomys achieves CNS functional recovery, an ability unmatched by any other known mammal, may ultimately guide strategies to enhance repair in nonregenerative mammals, including humans.

Cinnamoylquinic acid derivatives, namely, 3,4,5-tri-caffeoylquinic acid (TCQA) and its structurally modified analogue, 3,4,5-tri-feruloylquinic acid (TFQA), have demonstrated promising neuroprotective and pro-neurogenic activities. However, it remains unclear how the substitution of caffeoyl groups with feruloyl groups influences their molecular activity. Therefore, we performed an integrated multi-omics analysis, combining post hoc transcriptomic profiling of TCQA- and TFQA-treated neural stem cells (NSCs) isolated from 6 to 8-week-old adult male ICR mouse brains with targeted metabolomic analysis in SH-SY5Y neuroblastoma cells. We applied an interaction-only nested linear model, which revealed gene sets uniquely responsive to TFQA compared with TCQA. TFQA elicited broader pathway enrichment involving cell signaling, immune modulation, and metabolic regulation, whereas TCQA produced narrower transcriptional shifts. Nested comparative modeling identified 709 genes differentially regulated between TFQA and TCQA, with TFQA uniquely enriching pathways such as glutamatergic synapse, long-term potentiation, TRP channel regulation, and apelin signaling. Downregulation of cell cycle-related pathways and cytokine secretion suggested that TFQA promotes neuronal differentiation while reducing inflammatory activity. Metabolomic profiling further demonstrated TFQA-specific alterations in central energy metabolism, redox balance, amino acid utilization, and neurotransmitter-related metabolites. TCQA showed carbohydrate metabolism and glycan turnover. Integrated pathway analysis and gene-metabolite network modeling revealed coordinated TFQA-associated molecular reprogramming, with metabolites such as ATP, GTP, glutamate, GABA, and L-arginine emerging as central hubs linking transcriptomic and metabolic responses. Collectively, this study provides a multi-layered, systems-level comparison of TCQA and TFQA across a cross-species, cross-cell-type framework, revealing both conserved and divergent molecular responses and offering insights into the structure-activity principles shaped by feruloyl substitution.

Critical-sized bone defects still present significant clinical challenges because traditional bone graft methods have noticeable limitations.

Yes-associated protein (YAP) signaling is a key regulator of intestinal epithelial regeneration and drives fetal-like reprogramming that generates revival stem cells (revSC). Because YAP activity is sensitive to extracellular matrix properties and substrate stiffness, we asked whether a stiff plastic substrate could provide a mechanically defined platform to induce a revSC-like state in vitro. We established Matrigel-derived murine small intestinal organoids cultured in Wnt-containing medium, dissociated them into single cells, and plated them onto collagen I/IV-coated plastic plates to generate a two-dimensional (2D) monolayer. The resulting monolayer formed a continuous, proliferative epithelial sheet with abundant Ki67-positive cells. Immunostaining revealed ubiquitous nuclear retention of YAP. RT-qPCR showed induction of canonical YAP target genes (Ctgf, Cyr61, Ankrd1) and upregulation of revSC markers (Ly6a, Clu), accompanied by marked suppression of crypt basal columnar (CBC) markers (Lgr5, Ascl2, Olfm4), compared with a homeostatic Matrigel organoid control. Notably, after withdrawal of the Wnt3a alternative peptide PG-008 from day 3 onward, the 2D monolayer remained viable through day 8 and retained elevated Ly6a and Clu expression, while CBC and all other differentiated lineage markers (Alpi, Defa6, Muc2, Chga) remained strongly repressed. These findings establish a plastic-based 2D monolayer as a complementary in vitro revSC model characterized by high YAP activity and sustained revSC-like properties with reduced dependence on exogenous Wnt stimulation.

Friedreich's ataxia (FRDA) is a multisystem, autosomal recessive disease caused by biallelic expansion of GAA repeats in intron 1 of the frataxin gene (FXN). While ∼96% of FRDA patients carry expanded GAA repeats on both FXN alleles, ∼4% are compound heterozygous with expanded GAA repeats on one allele and another mutation on the second allele. We generated induced pluripotent stem cells from blood lymphocytes from a FRDA patient carrying the FXN c.165 + 5G > C point mutation, which interferes with canonical splicing of intron 1 of the FXN gene. These cells allow for development of therapeutic approaches that target splicing defect in FRDA.

CD8αα+TCRαβ+ intraepithelial lymphocytes (IELs) play crucial roles in maintaining intestinal homeostasis and host protection. However, the functional regulation of these cells remains unclear. Here, we have discovered and characterized two distinct developmental stages within intestinal CD8αα+ αβ IELs: a stem-like, defined by BCL6, TCF1, and CD160 expression, and an effector-like, with granzyme B expression and Prdm1 transcription. The differentiation from stem-like to effector-like CD8αα+ αβ IELs is promoted by T cell receptor (TCR) and IL-12 signaling and is controlled by the opposing actions of BCL6 and BLIMP1. Loss of BCL6 promotes the development of effector-like CD8αα+ αβ IELs, leading to increased effector molecule expression and heightened inflammation under dextran sodium sulfate (DSS)-induced colitis. In contrast, BLIMP1 deficiency perturbs the effector differentiation and reduces the susceptibility to gut inflammation. Our study thus reveals a critical antagonistic function between BCL6 and BLIMP1 in governing the fate decisions of CD8αα+ αβ IEL subsets.

To dissect how malignant versus infectious pleural disease reshapes local and systemic immunity, we compared lung adenocarcinoma with tuberculosis using matched pleural effusions and peripheral blood from patients and healthy controls using single cell transcriptome analysis and TCR clonotype tracking. Th1/17 polarized pro-inflammation dominating TB effusions, while their precursors, the recently activated CD4 T cells, adopt an antitumor trajectory in LUAD, but their recruitment and clonal expansion were effectively suppressed. In both diseases, CD8⁺ T cells diverged into GZMH⁺ and GZMK⁺ subsets. The former served as the antitumor killer cells but suppressed by multiple anti-inflammatory signals especially from the extracellular matrix in LUAD. The later could serve as stem-like precursors. MAITs and class-switched B cells both exhibited higher levels of activation and expanded in TB. Myeloid cells were mostly recovered from peripheral bloods and showed heightened activation in TB, upregulating TNFRSF14, TNFRSF13B, and pro-inflammatory cytokines (CXCL2, CXCL3, IL1), while LUAD featured immunosuppressive signals including MDK-NCL, FN1-CD44, and THBS1-CD47. Cell-cell communication highlighted LUAD-enriched outgoing interaction strengths by myeloid cells including monocytes and DCs, through IL16 and VISFATIN signaling, which strongly corelated with survivals. In conclusion, both pleural effusions and peripheral blood from TB and LUAD exhibit significant distinct immune landscapes. These results delineate disease-specific molecular mechanisms underlying immune regulation in pleural malignancies and infections.