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PubMed2026

Rapid derivation of cloning-competent cells from peripheral blood advances conservation biobanking.

Establishing viable cell lines from endangered species is essential for conservation, yet traditional fibroblast derivation from skin biopsies faces challenges including contamination risk and extended culture timelines. Here, we demonstrate that endothelial progenitor cells (EPCs) and pericytes isolated from peripheral blood represent robust alternatives to fibroblasts for biobanking. Compared to canid fibroblasts, canid blood-derived cells exhibit 2- to 3-fold faster doubling rates (15 to 20 h vs. ~35 h for fibroblasts) and reduced time to banked cell lines (1.5 to 2 wks vs. 3 to 4 wks for fibroblasts). Proteomic profiling of 32 canonical markers confirmed EPCs and pericytes represent distinct populations with lineage-specific molecular signatures. Optical genome mapping demonstrated equivalent genomic stability across cell types with no detectable structural variants or aneuploidies. Finally, interspecific somatic cell nuclear transfer (iSCNT) experiments confirmed both EPCs and pericytes generate viable canid embryos with efficiency meeting or exceeding fibroblasts. As a proof of concept for conservation cloning, iSCNT embryos made with gray wolf blood-derived cells had a 15% implantation rate following embryo transfer and resulted in six viable fetuses. These findings support integrating blood-derived cell banking into conservation programs, which enables opportunistic genetic preservation during standard management activities and expands options for genetic rescue through assisted reproductive technologies.

Animals↗

PubMed2026

Genomic and epigenetic regulatory mechanisms in exercise-based rehabilitation processes: Cellular and tissue remodeling, microvascular adaptation, and circulating biomarkers.

While exercise-based rehabilitation is known to positively impact functionally related parameters, the role of genomic and epigenomic responses coordinated with cellular, extracellular matrix (ECM), mitochondrial, and microvascular adaptations remains insufficiently investigated. This narrative review summarizes mechanistic evidence linking exercise-associated mechanical, metabolic, hypoxia-redox, inflammatory, and hemodynamic stimuli with tissue remodeling and clinically relevant biomarkers. Current findings indicate that integrin-focal adhesion kinase (FAK) signaling and Hippo YAP/TAZ pathways contribute to mechanical signal transduction, cytoskeletal regulation, and gene expression, whereas metabolic adaptation, ATP homeostasis, and protein synthesis are regulated through AMPK-PGC-1α, SIRT1, and mTOR-dependent pathways. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA regulation, further influence cell-specific responses in myofibers, satellite cells, fibro-adipogenic progenitors, endothelial cells, pericytes, and immune cells. In addition, VEGF-VEGFR2, eNOS-NO, and KLF2/KLF4 signaling, together with extracellular matrix turnover and inflammation resolution, contribute to tissue repair and microvascular adaptation during rehabilitation. Importantly, acute exercise-induced molecular responses should not be interpreted as direct evidence of sustained tissue adaptation. Circulating microRNAs, extracellular vesicles, cell-free DNA, collagen-related markers, and vascular proteins represent promising approaches for monitoring rehabilitation-related changes; however, their clinical translation remains limited by challenges related to tissue specificity, biomarker kinetics, analytical variability, and the need for standardized validation alongside structural and functional outcomes.

AMPK–PGC-1α signaling↗

PubMed2026

Transverse Tibial Transport for Limb Salvage in Ischemic Lower Extremity Disease: Technique, Mechanisms, and Clinical Outcomes-A Systematic Review.

Transverse tibial transport (TTT) is a surgical technique derived from Ilizarov's distraction osteogenesis principles that stimulates angiogenesis and microcirculatory regeneration in the ischemic lower limb without directly manipulating macrovascular anatomy. By creating a proximal tibial cortical bone window and distracting it transversely using an external fixator, TTT triggers converging cascades of growth factor release, endothelial progenitor cell mobilization, and immunomodulation that translate into improved distal limb perfusion and wound healing. Combined TTT plus endovascular therapy improves amputation-free survival versus endovascular therapy alone. Prospective randomized trials and standardized international protocols are needed to consolidate TTT's role in multidisciplinary limb salvage pathways.

Humans↗

PubMed2026

RNA Binding Protein PCBP1 Functions in the Endothelial-to-Hematopoietic Transition During Hematopoietic Stem Cell Formation.

Two paralogous RNA-binding proteins, PCBP1 and PCBP2, are individually essential for mouse development. Pcbp2-null embryos lose viability at midgestation, whereas Pcbp1-null embryos have an earlier, peri-implantation lethality. Inactivation of each gene alone in the differentiating erythroid lineage failed to impact embryonic viability, whereas combined Pcbp1/Pcbp2 inactivation resulted in repression of erythroid/hematopoietic gene expression midgestation, decreased blood cell formation, and fetal demise. Here, we assess the impacts of individual and combined conditional inactivation of Pcbp1 and Pcbp2 in endothelial cells on embryonic hematopoietic stem and progenitor cell (HSPC) formation. Inactivation of Pcbp1 in endothelial cells is embryonic lethal and reduces the number of HSPCs, whereas loss of Pcbp2 has no impact. Combined deletion of Pcbp1 and Pcbp2 in endothelial cells results in a more severe phenotype than loss of Pcbp1 alone. These results demonstrate that although Pcbp1 is a major regulator of HSPC formation, the two genes have nonredundant roles in endothelial cells.

Animals↗

PubMed2025

Self-organization of sinusoidal vessels in pluripotent stem cell-derived human liver bud organoids.

The induction of tissue-specific vessels in in vitro living tissue systems remains challenging. Here, we directly differentiated human pluripotent stem cells into CD32b+ putative liver sinusoidal progenitors by dictating developmental pathways. By devising an inverted multilayered air-liquid interface culture, hepatic endoderm, septum mesenchyme, arterial and sinusoidal quadruple progenitors self-organize to generate and sustain hepatocyte-like cells neighboured by divergent endothelial subsets composed of CD32blowCD31high, LYVE1+STAB1+CD32bhighCD31lowTHBD-vWF- and LYVE1-THBD+vWF+ cells. WNT2 mediates sinusoidal-to-hepatic intercellular crosstalk potentiating hepatocyte differentiation and branched endothelial network formation. Intravital imaging reveals the iPS-cell-derived putative liver sinusoidal endothelial progenitor develops fully perfused human vessels with functional sinusoid-like features. Organoid-derived hepatocyte- and sinusoid-derived coagulation factors enable correction of in vitro clotting time with Factor V-, VIII-, IX- and XI-deficient plasma, and rescues the severe bleeding phenotype in haemophilia A mice on transplantation. Advanced organoid vascularization technology allows for interrogating key insights governing organ-specific vessel development, paving the way for coagulation disorder therapeutics.

Humans↗

PubMed2026

Endothelial PERK restricts lymphoid regeneration by reducing DLL4-NOTCH3 signaling at the Pre-B niche.

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome. We study the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We reveal that BM endothelium PERK activation is a prominent feature of patients with leukemia and is a hallmark response in mice following ionizing irradiation. Ablating endothelial Perk boosts NOTCH ligand DLL4 expression and promotes DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis reveals that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment. NOTCH3 is critical for the upregulation of IL7 following irradiation and the expansion of lymphoid progenitors. These findings not only unveil an ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising strategy to improve immune recovery after myeloablative transplantation.

CP: cell biology↗

PubMed2026

Tropomyosin 1 Promotes Platelet Adhesion and Clot Contraction Separate from Its Roles in Developmental Hematopoiesis.

Genome-wide association studies (GWAS) link the Tropomyosin 1 (Tpm1) locus to quantitative blood trait variation, but related mechanisms are unclear. Tpm1 encodes an actin-binding protein that regulates actin filament diversity, cell adhesion, signaling, and actomyosin contractility. Murine Tpm1 deficiency enhances hemogenic endothelial cell (HEC) specification, but it was unclear if these effects extended to postnatal hematopoiesis. We used Cdh5Cre and VavCre models to conditionally knock out Tpm1 (Tpm1KO) in endothelial anor hematopoietic cells. Both models ablate Tpm1 in postnatal blood. Endothelial Tpm1KO increases HEC specification without altering hematopoietic progenitor cell production or adult blood counts, suggesting separate roles for Tpm1 in the embryonic and adult blood systems. Tpm1KO increases adult platelet lifespan and diminishes adhesion to fibronectin and fibrinogen. Chemical Tpm1 inhibition also reduces focal adhesion in murine and human platelets. Altered platelet morphology and reduced platelet spreading suggest perturbed actomyosin contractility underlies these findings. Platelet fibrin binding promotes blood clot contraction, which reduces occlusive thrombosis. Tpm1KO limits clot contraction and worsens vascular occlusion in ferric chloride-induced stroke models. In addition to offering a mechanistic explanation for why genetic variation at the TPM1 alters platelet traits in GWAS, our findings reveal novel roles for Tpm1 in clot contraction and thrombosis.

Animals↗

PubMed2025

Zonal endothelial cell heterogeneity underlies murine renal vascular development.

The renal vasculature consists of highly specialized blood vessels with distinct physiological functions. Defining their transcriptional signatures and tracing their developmental ontogeny has thus far been challenging due to a lack of regionally specific endothelial biomarkers. Here, we performed single nuclear RNA sequencing (snucRNA-Seq) to interrogate the transcriptional heterogeneity of embryonic renal endothelial cells (ECs). We identified ten endothelial subtypes, and validated regionally restricted expression of novel marker genes of glomeruli, arteries, vasa recta, and immature capillary subtypes using multiplex RNAscope. We also define previously uncharacterized and heterogeneous molecular signatures of the immature renal vasculature, including putative endothelial progenitors. We interrogate biological characteristics of immature EC types using a variety of in vivo tools. Lineage tracing of Esm1-expressing cells reveals the previously unrecognized multi-origin and multi-clonal endothelial tip cell contribution to the glomerular vasculature. Together, this study provides a validated, tool-focused developmental atlas of the murine renal vasculature and elucidates novel cellular mechanisms of nephron vascularization.

Animals↗

PubMed2025

Alcohol-induced KDM5B activation in hepatocytes drives pathogenic cell-cell communication, leading to loss of liver function.

BACKGROUND: Alcohol-associated liver disease (ALD) is a major cause of alcohol-associated mortality. Previously, we identified KDM5B as a sex-specific mediator of ALD development; however, the mechanism behind KDM5B-induced pathological changes is not established. METHODS: Kdm5b flox/flox female mice were fed a western diet and 20% alcohol in the drinking water for 8-16 weeks (WDA). To induce KO, mice received 2×1011 genome copies of AAV8-CMV-Cre, AAV8-TBG-Cre, or AAV8-control. To test the role of myeloid C/EBPβ, Cebpbfl/fl, or Cebpbfl/fl Lyz2-Cre mice were fed WDA for 16 weeks. RESULTS: We found that Kdm5b KO prevented alcohol-induced liver fibrosis and liver inflammation in female mice. These changes were in part mediated by hepatocyte-to-non-parenchymal cell communication changes. KDM5B in hepatocytes promoted pro-inflammatory and pro-fibrotic changes in liver macrophages, endothelial cells, and stellate cells. Moreover, KDM5B promoted alcohol-induced early increase in EpCAM-positive liver progenitors and loss of liver function at later time points of alcohol feeding. We found that loss of liver function was dependent on a hepatocyte-to-macrophage communication feedback loop. KDM5B in hepatocytes inhibited macrophage C/EBPβ expression, which in turn resulted in loss of the mature KCs phenotype and prevented the ability of KCs to support hepatocyte differentiation, ultimately leading to loss of liver synthetic function. CONCLUSIONS: KDM5B activation in hepatocytes drives pathogenic cell-cell communication, leading to alcohol-induced loss of liver function in ALD.

Animals↗

PubMed2026

Atherosclerotic plaque fibroblasts derive from adventitial and medial Pdgfra-lineage-positive cells and predominantly maintain fibroblast identity.

AIMS: Fibroblasts are mesenchymal cells in the healthy vascular adventitia. In atherosclerosis, single-cell sequencing datasets suggest fibroblasts are abundant in plaques. However, their identity, origin, and fate during plaque progression remain unclear, which we aim to unravel here. APPROACH AND RESULTS: To robustly define fibroblast identity, origin, and fate, we employed meta-analyses of 54 single-cell RNA sequencing libraries, including murine smooth muscle cell (Myh11) and endothelial cell (EC) (Cdh5) lineage reporter mice with and without atherosclerosis; human control and atherosclerotic arteries; and murine adventitia and atherosclerotic plaques processed separately from low-density lipoprotein (LDL) receptor knockout (Ldlr-/-) mice. These meta-analyses showed that murine and human plaque fibroblast identity was robustly defined by Pdgfra, Pi16, Cygb, and Serpinf1 mRNA. Ninety-five percent of plaque fibroblasts do not derive from the Myh11 lineage, while no Cdh5-lineage-positive cells were present in the fibroblast cluster. We identified five murine arterial fibroblast subsets in atherosclerotic murine aorta: progenitor fibroblasts, matrix fibroblasts, inflammatory fibroblasts, an EC-like fibroblast subset, detected in both adventitia and plaques, and Col5a3+ fibroblasts, unique to the adventitia. We next studied fibroblast identity, origin, and fate using pseudotime analysis and Pdgfra-CreERT2/tdTomato lineage reporter mice (Pdgfra Lin+). Healthy Pdgfra Lin+ reporter mice showed predominant adventitial tdTomato expression, and infrequent medial and intimal Pdgfra Lin+ cells co-expressing MYH11 and PECAM1, respectively. The Pdgfra Lin+ plaque area increased with diet duration. Pdgfra Lin+ cells largely maintain fibroblast identity in the plaque, while <10% co-express SMC markers (MYH11, SM22α), or contribute to ACTA2+ cap cells. ECs gaining mesenchymal markers are transcriptionally distinct from Cdh5-lineage-negative fibroblasts gaining EC markers. Plaque-resident EC-like fibroblasts displayed a mesenchymal-to-endothelial transition transcriptome, which was induced in human primary fibroblasts in vitro by starvation, and dampened or reversed by IL1B, TGFB1, TGFB3, and oxidized LDL. Cross-species integration showed that all murine plaque fibroblasts were conserved in human atherosclerosis, with one additional subset partially resembling murine subsets, and three human-specific subsets. Importantly, human fibroblast subsets differentially correlated to human plaque traits, with EC-like fibroblasts correlating to plaque instability. CONCLUSION: Our results indicate that 95% of plaque-residing fibroblasts are Myh11 Lin- Plaque fibroblasts have a dual origin, predominantly adventitial Pdgfra Lin+ progenitor fibroblasts, with a minor contribution from medial Pdgfra Lin+  Myh11+ SMCs. Most plaque fibroblasts maintain fibroblast identity. Murine plaque fibroblast subsets were conserved in human atherosclerosis. EC-like fibroblasts are linked to human plaque instability. Intervening in progenitor-to-specific fibroblast transitions could present a new avenue to promote plaque stability in atherosclerosis.

Atherosclerosis↗

PubMed2023

Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging.

Reactivation and dysregulation of the mTOR signaling pathway are a hallmark of aging and chronic lung disease; however, the impact on microvascular progenitor cells (MVPCs), capillary angiostasis, and tissue homeostasis is unknown. While the existence of an adult lung vascular progenitor has long been hypothesized, these studies show that Abcg2 enriches for a population of angiogenic tissue-resident MVPCs present in both adult mouse and human lungs using functional, lineage, and transcriptomic analyses. These studies link human and mouse MVPC-specific mTORC1 activation to decreased stemness, angiogenic potential, and disruption of p53 and Wnt pathways, with consequent loss of alveolar-capillary structure and function. Following mTOR activation, these MVPCs adapt a unique transcriptome signature and emerge as a venous subpopulation in the angiodiverse microvascular endothelial subclusters. Thus, our findings support a significant role for mTOR in the maintenance of MVPC function and microvascular niche homeostasis as well as a cell-based mechanism driving loss of tissue structure underlying lung aging and the development of emphysema.

Mice↗

PubMed2022

S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer.

Sustained oxidative stress in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustained CSF1R inhibition (CSF1Ri) is limited as a monotherapy. We hypothesized that one of the underlying causes for the reduced efficacy of CSF1Ri and increased oxidation in CRPC is the upregulation and uncoupling of endothelial nitric oxide synthase (NOS3). Here we show that in high-grade PCa human specimens, NOS3 abundance positively correlates with CSF1-CSF1R signaling and remains uncoupled. The uncoupling diminishes NOS3 generation of sufficient nitric oxide (NO) required for S-nitrosylation of CSF1R at specific cysteine sites (Cys 224, Cys 278, and Cys 830). Exogenous S-nitrosothiol administration (with S-nitrosoglutathione (GSNO)) induces S-nitrosylation of CSF1R and rescues the excess oxidation in tumor regions, in turn suppressing the tumor-promoting cytokines which are ineffectively suppressed by CSF1R blockade. Together these results suggest that NO administration could act as an effective combinatorial partner with CSF1R blockade against CRPC. In this context, we further show that exogenous NO treatment with GSNOR successfully augments the anti-tumor ability of CSF1Ri to effectively reduce the overall tumor burden, decreases the intratumoral percentage of anti-inflammatory macrophages, myeloid-derived progenitor cells and increases the percentage of pro-inflammatory macrophages, cytotoxic T lymphocytes, and effector T cells, respectively. Together, these findings support the concept that the NO-CSF1Ri combination has the potential to act as a therapeutic agent that restores control over TME, which in turn could improve the outcomes of PCa patients.

Cysteine↗

PubMed2025

Hypoxia-inducible factor 2 regulates alveolar regeneration after repetitive injury in three-dimensional cellular and in vivo models.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional "aberrant" epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells. Using mouse genetic lineage-tracing strategies together with scRNA-seq, we found that these disease-emergent aberrant epithelial cells predominantly arose from airway-derived (Scgb1a1-CreER-traced) progenitors and exhibited transcriptional programs of Hif2a activation. In mice treated with repetitive intratracheal bleomycin, deletion of Epas1 (Hif2a) but not Hif1a, from airway-derived progenitors, or administration of the small-molecule HIF2 inhibitor PT-2385, using both prevention and rescue approaches, attenuated experimental lung fibrosis, reduced the appearance of aberrant epithelial cells, and promoted alveolar repair. In mouse alveolar organoids, genetic or pharmacologic inhibition of Hif2 promoted alveolar differentiation of airway-derived epithelial progenitors. In addition, treatment of human distal lung organoids with PT-2385 increased colony-forming efficiency, enhanced protein and transcriptional markers of alveolar type 2 epithelial cell maturation, and prevented the emergence of aberrant epithelial cells. Together, these studies showed that HIF2 activation drives the emergence of aberrant epithelial populations after repetitive injury and that targeted HIF2 inhibition may represent an effective therapeutic strategy to promote functional alveolar repair in IPF and other interstitial lung diseases.

Animals↗