Endothelial cell dysfunction and loss are key drivers of acute and chronic liver disease, underscoring a critical unmet need for liver vascular-targeted therapies. Liver sinusoidal endothelial cells are specialized endothelial cells that form a fenestrated microvascular niche regulating hepatocyte metabolism, immune homeostasis, and hepatic stellate cell activation. Repopulating this niche through transplantation of primary liver sinusoidal endothelial cells, endothelial progenitor cells, induced-pluripotent stem cell-derived liver sinusoidal endothelial cells, or engineered endothelial cells delivered within biomaterial aims to restore microvascular architecture, reestablish supportive angiocrine signaling, attenuate fibrosis, and promote liver regeneration. This review summarizes the biological rationale for endothelial cell-based therapy, compares cell sources and engineering strategies, evaluates cell delivery and engraftment approaches, and synthesizes preclinical evidence demonstrating therapeutic benefits across diverse animal models of liver injury. Finally, we highlight key translational challenges and propose future directions to accelerate the clinical development of endothelial cell-based therapies for liver disease.

The regulation of mesenchymal stem cell (MSC) differentiation is a complex process influenced by multiple factors, among which autophagy has emerged as a key determinant of stem cell fate. Here, we investigated its role in MSC differentiation into hepatocyte-like cells. Autophagy was first assessed during basal hepatic differentiation of adipose tissue-derived MSCs (AD-MSCs) in the absence of modulators. Subsequently, we evaluated the impact of autophagy modulation by chemical agents on the functionality of the derived hepatocyte-like cells. Isolated AD-MSCs were induced to differentiate, and hepatocyte formation was assessed by morphological, molecular, and biochemical analyses. Macroautophagy was examined via protein and mRNA expression of key autophagy‑related markers, supplemented with transmission electron microscopy (TEM) and acridine orange staining. To confirm the role of autophagy in hepatic differentiation, differentiating MSCs were subjected to autophagy induction by serum starvation or treatment with rapamycin (50nM), and inhibition using 3‑methyladenine (3‑MA, 5µM). Autophagy activation was observed during baseline differentiation (days 0, 7, 14, and 21 post-induction), as indicated by increased Beclin‑1, LC3B, and ATG7 expression; reduced p62; and accumulation of autophagic vacuoles confirmed by TEM and acridine orange staining. Induction of autophagy by rapamycin or serum starvation enhanced hepatic functional markers, as evidenced by higher levels of secreted albumin and urea, along with increased ALT and AST activities, whereas 3‑MA impaired these parameters. Collectively, these findings indicate that autophagy supports the acquisition of hepatic functional and metabolic characteristics in MSC‑derived hepatocyte-like cells, providing insight into its regulatory role during MSC differentiation toward hepatocyte-like cells.

Galectin-9 (Gal-9) is a tandem-repeat β-galactoside-binding lectin increasingly recognized as a context-dependent regulator of cancer biology that extends well beyond its canonical role as an immune checkpoint ligand. While Gal-9-mediated immune modulation (e.g., via TIM-3/VISTA) remains important, emerging evidence positions Gal-9 as an upstream organizer of tumor-intrinsic programs and microenvironmental crosstalk that shape angiogenesis, invasion and metastasis, therapy resistance, and maintenance of cancer stem-like states. These divergent outcomes are driven by multi-layered regulation of Gal-9, encompassing transcriptional and epigenetic control, post-translational modification, and context-specific processing/secretion, together with dynamic remodeling of the tumor glycome. In addition, Gal-9 signaling is contingent on cell type-specific receptor repertoires (e.g., TIM-3, VISTA, CD44 and related glycan-binding partners) across malignant, stromal, and immune compartments. This review proposes an integrated, mechanism-based framework to clarify why Gal-9 can exert either tumor-promoting or tumor-suppressive effects, depending on the cancer type and biological context. Rather than cataloging reported effects, we synthesize evidence to propose a context "decision model" in which Gal-9 activity is predicted by (i) the cellular source of Gal-9 (tumor cell vs myeloid/stromal compartments), (ii) Gal-9 biochemical state and post-translational processing, (iii) receptor expression and signaling competence of recipient cells, and (iv) the glycan landscape that governs ligand engagement. We further integrate these determinants with clinical observations to clarify why Gal-9 associates with opposite prognoses in different tumors, and we outline how this framework can stratify patients and guide therapeutic design. Finally, we evaluate Gal-9-targeted interventions-neutralizing antibodies, decoy receptors, and rational combinations with immunotherapy and standard modalities-through the lens of context dependence, highlighting actionable biomarkers and experimental readouts needed to translate Gal-9 biology into precision oncology.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is definitive, potential curative therapy for various hematological diseases. Poor graft function (PGF) remains a significant complication, characterized by persistent cytopenia despite complete donor chimerism. The bone marrow microenvironment, particularly endothelial cells expressing CD31 (PECAM-1), plays a crucial role in the maintenance and proliferation of hematopoietic stem cells. This study examines the expression of CD31 in the bone marrow endothelial microenvironment of patients with Poor Graft Function (PGF) are compared with those exhibiting Good Graft Function (GGF) following allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Paullinia pinnata Linn (Sapindaceae) is used in Cameroonian ethnomedicine for the treatment of arthritis. Its leafy aqueous (AEPP) and methanol (MEPP) extracts have shown potent preventive effects in mono-arthritis but their curative effects and their mechanism of action remain unknown.

Mammalian thyroid status is governed by thyroid secretion of L-thyroxine (T4) as a prohormone that is monodeiodinated in peripheral tissues to bioactive T3 (3,5,3'-triiodo-l-thyronine). T4 secretion is controlled by the hypothalamic-pituitary-thyroid (HPT) axis (central control) whereas T3 availability to target cells depends mainly on mechanisms in extrathyroidal tissues such as cellular transport and deiodination (peripheral control). Does this model apply to poikilothermic teleost fish which in contrast to homeothermic mammals may show major surges in plasma T4 due to season, feeding, reproductive state or stressors? We have evaluated the contributions of central and peripheral mechanisms to fish thyroid status in light of recent discoveries employing both traditional endocrine approaches and more modern molecular biological techniques, focusing primarily on salmonid species which may undergo a unique thyroid-implicated premigratory parr-smolt transition (PST), and which as tetraploids may express multiple paralogs of regulatory peptides. Most teleost research has focused on peripheral control by the three classic deiodinases (D1, D2 and D3). In salmonids they determine systemic (D1, D2) and tissue-specific (D2) T3 generation from T4 and the equally critical T4 and T3 degradations (D1, D3). Tetraploid salmonids may express up to four paralogs for a given deiodinase, providing the potential for species-specific or tissue-specific T3 production, curtailment of T3 action, or iodine recapture. Critical as they appear, salmonid deiodinases do not function in isolation but in concert with, and dependence on, TH plasma transport, cell-membrane translocation, hepatic conjugation, biliary excretion and gastrointestinal metabolism. Two rainbow trout properties are particularly distinct from the mammalian model: i) T3, but not T4, exchanges rapidly between plasma and erythrocytes permitting plasma T3 stability despite marked acute changes in plasma T4 and ii) in contrast to ingested T4, which is unavailable from food due to complete gastrointestinal deiodination, ingested T3 contributes to the plasma T3 pool. Thus the teleost liver, poised at the confluence of exogenous and endogenous T3 sources, may play a strategic role through its TH biliary excretion, deiodination and other pathways in regulating systemic T3 availability involved in anabolic/catabolic balance and somatic growth. A major consequence of ingested T4 degradation is the exclusive delegation of T4 availability to the HPT axis. Since mammalian TSH consistently stimulates teleost T4 secretion a mammal-like HPT central control model has been assumed. However, teleost HPT function differs from that of homeotherms in both its hypothalamic control and response to external stimuli. T4 secretion could be regulated mainly by T4 negative feedback with the HPT axis playing a subsidiary role of merely ensuring adequate T4 substrate for regulated peripheral deiodination to proceed. However, this does not account for the notable surges in salmonid plasma T4 and implies resetting of the HPT 'thyrostat'. Thus the role of central TSH control in the regulation of plasma T4 changes remains unclear, awaiting further characterization of endogenous TSH secretion. Furthermore, discoveries of TSH-subunit and TSH-receptor expression in piscine peripheral tissues such as the CNS, liver, and gonad require reassessment of TSH function with a focus not only on its traditional endocrine actions but also on its potential as a paracrine regulator of TH action in peripheral tissues. In conclusion, while there are many similarities in thyroid regulation between mammals and salmonids there are also key differences. These likely stem from the evolution of homeothermy, the constraints of terrestrial iodine availability and a plasticity in salmonid peripheral and central control resulting from tetraploidy.

In this issue of Developmental Cell, Vijaykumar et al. interrogate the fetal liver (FL) hematopoietic stem and progenitor cell (HSPC) niche using 3D quantitative microscopy, fluorescent genetic reporters, and transcriptomics, thereby illuminating important HSPC support cells and mechanisms impacting HSPC FL egress across this window of ontogeny.1.

The colonic epithelium is organized in functional regions and interacts with an abundant microbial community. In Cell, Rispal et al. discover that regionalization depends on microbes, with proximal identity regulated by microbial nicotinic acid-induced PPARα activation in the epithelium. Changes in tissue identity reshape zones of tissue injury.

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal neoplasms of the digestive tract, are primarily driven by mutations in KIT/PDGFRA. The remarkable success of tyrosine kinase inhibitors such as imatinib (IM) in treating GIST has established them as a paradigm of precision medicine in modern oncology. However, acquired resistance to IM remains a major cause of poor prognosis in GIST patients. Exploring novel mechanisms of IM resistance is critically important for improving outcomes. Tumor dormancy and cancer stem cell (CSC) models, observed across multiple malignancies, are closely linked to therapy resistance, tumor recurrence, and metastasis. Emerging evidence suggests that analogous non-genetic persistence states also exist in GIST, including dormant cells and KITlow stem-like/CSC-like subpopulations. This review summarizes the fundamental regulatory mechanisms of tumor dormancy and CSC biology, discusses their candidate manifestations in GIST, and proposes innovative therapeutic strategies based on these insights.

The Joel A. DeLisa Lecture on regenerative rehabilitation was presented by Dr. Thomas Rando on February 27, 2025, at the Association of Academic Physiatrists Annual Scientific Meeting. This article follows the key themes presented in that lecture, exploring the regenerative potential of exercise as a biophysical stimulus and focusing on its ability to modulate muscle stem cell (MuSC) function and enhance tissue repair following muscle injury. In aged mice, exercise restores youthful properties to MuSCs, thereby enhancing regenerative capacity that declines with age. In models of volumetric muscle loss (VML), exercise improves the engraftment and integration of transplanted MuSCs by promoting myogenesis, angiogenesis, and reinnervation. Additionally, exercise shifts systemic and local immune responses toward a pro-regenerative state, enhancing stem cell function across multiple tissues. Exercise acts as a potent, non-invasive regenerative intervention with direct effects on stem cell biology and tissue repair. These findings highlight the potential for integrating exercise-based rehabilitation with emerging biologic therapies in clinical practice, offering new strategies for improving recovery after injury. In this context, physiatrists and physical therapists will play a central role in the emerging field of regenerative rehabilitation.

Critical-sized bone defects (CSD) remain a major clinical challenge due to three interrelated barriers: inadequate mechanical support, insufficient osteogenic induction, and impaired angiogenesis, all of which hinder effective regeneration. To tackle these, we developed a dual-network bioactive scaffold, ermd bFGF@CB-gel, based on a chondroitin sulfate methacryloyl/bacterial cellulose gel (CB-gel) which synergistically combines three key properties: i) a photocurable biomimetic mineralized scaffold (CB-gel) for in situ bone repair with mechanical support and a bone-ECM-mimicking microenvironment for delivering bone marrow mesenchymal stem cells (BMSCs); ii) a bio-nano carrier (BC) for sustained release of bFGF which enhances the adhesion and proliferation via EGFL/Itga2b pathway, strengthens osteogenic differentiation and mineralization by activating the COMP/PI3K/AKT pathway of rat BMSCs; iii) bFGF released by the dual-network promotes migration and angiogenesis of microvascular endothelial cells by combining FGFR to activate the PI3K/AKT/eNOS pathway. In a rat CSD model, the bFGF@CB-gel achieved a statistically significant increase in new bone volume, as quantified by micro-CT, and enhanced vascular density, evaluated via immunohistochemical staining. These findings highlight the potential of bFGF@CB-gel as an effective local delivery system of BMSCs via linking biomechanics, molecular signaling, and cellular activity, which moves beyond simplistic function stacking to a rational, synergistic design for bone regeneration in CSD, addressing key challenges in reconstructive surgery.

Therapeutic angiogenesis (TA) is a promising strategy for treating ischemic diseases, mainly by targeting the angiogenesis pathways and cells, particularly VEGF and endothelial progenitor cells. Although stem cell therapy has been extensively investigated, its clinical translation remains limited by challenges such as poor cell retention, low survival rates, and inefficient integration. In this review, we propose a mechanism-based framework of angiogenesis to discuss how biomaterials act synergistically with stem cells mainly through two distinct pathways: enhancing paracrine capacity and promoting direct differentiation of vascular lineage cells for vascular repair. Firstly, we go through the scientific literature and clinical studies, and summary the researches on biomaterials serve as artificial microenvironments to improve the retention and secretory function of mesenchymal stem cells (MSCs) and adipose-derived stem cells (ADSCs), thereby maximizing the release of angiogenic factors such as VEGF, bFGF, NGF, microRNA and so on. Secondly, we explore how functionalized biomaterials guide the in situ recruitment of endothelial progenitor cells (EPCs) and support the structural maturation of induced pluripotent stem cell (iPSC)-derived endothelial cells. By integrating these mechanism-driven approaches, we offer new perspectives on future directions for preclinical research and clinical translation of biomaterial-based therapies. Overall, this review has examined the role of individual stem cells and biomaterials, especially enhanced angiogenesis by stem cells focusing on their mechanisms of action and preclinical and clinical applications. We further discussed the challenges encountered by stem cell therapy in advancing to the stage of clinical transformation and considered future prospects.

Mitochondria are increasingly recognized as central regulators of vascular health, shaping endothelial cell function through roles that extend far beyond energy production. In addition to coordinating redox balance, calcium dynamics, and biosynthetic support, recent studies have revealed that mitochondria participate in intercellular communication, with evidence of transfer events emerging in vascular contexts. Parallel efforts have advanced the deliberate delivery of exogenous mitochondria from preclinical proof-of-principle studies to first-in-human trials, demonstrating that freshly isolated organelles can be harvested and administered in real-time to critically ill patients with favorable early outcomes. The mechanisms underlying these benefits remain incompletely defined, and strategies for efficient and scalable delivery are still emerging. In this review, we prioritize recent evidence linking mitochondrial function to endothelial cell physiology, highlight the nascent but growing field of mitochondrial transfer in the vasculature, and examine how mitochondrial transplantation is evolving from experimental concept to clinical translation. Together, these advances point to new therapeutic avenues for preserving vascular integrity and treating disease.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have potential applications in treating cardiovascular disease but are currently limited in their clinical translation. This can be attributed in large part to the complex molecular and cellular interactions that underly cardiac differentiation, with current differentiation approaches yielding heterogeneous outcomes due to inadequate understanding and control of these interactions. We hypothesize that clonal lineage-dependent responses to differentiation contribute to these heterogeneous outcomes, and as such cardiac differentiations can be improved by tracking and controlling for hiPSC clonal heterogeneity, a variable often overlooked in current differentiation approaches. "Fate priming", wherein clonal lineage identity determines differentiation fate, has been demonstrated in other stem cell differentiation pathways. We investigated fate priming in hiPSC cardiac differentiation using the ClonMapper cell barcoding platform to label, track, and isolate distinct hiPSC lineages from the same cell line. We show that certain hiPSC lineages preferentially differentiate into hiPSC-CMs or non-CMs. After isolating lineages with apparent fate priming, we found significant differences in cardiac differentiation outcomes between these single-clone populations and heterogeneous, multi-clone hiPSC populations. These findings indicate that lineage identity influences hiPSC cardiac differentiation outcomes.

Radiation therapy induces DNA damage primarily through reactive oxygen species, leading to cancer cell apoptosis. However, intratumoral heterogeneity and spatial dose variations often result in the survival of polyploid giant cancer cells (PGCCs), a therapy-resistant subpopulation characterized by multinucleation, genetic instability, and stem-like features. Particularly in malignant breast cancer, PGCCs contribute to recurrence by adopting a dormant yet invasive phenotype. Despite their clinical relevance, reliable tools to identify or characterize these cells remain lacking. Here, we present a nanomechanical single-cell profiling platform that enables high-resolution mechanomics of radiation-induced PGCCs. Through integrated cytoskeletal imaging and nanoscale stiffness mapping, we identify a distinct mechanical dormancy state, marked by cortical actin remodeling, nuclear enlargement, and biomechanical stiffening. This dormant mechanotype is coupled with suppressed proliferation yet sustained expression of invasion-associated markers, representing a latent therapeutic threat. Our findings position mechanical dormancy as a mechanobiological hallmark of radiation resistance and propose a predictive framework for optimizing radiotherapy thresholds. This platform enables mechanotype-guided stratification and precision-targeted intervention in radiation-refractory cancer.

Exagamglogene autotemcel (exa-cel) is a one-time nonviral gene-edited therapy approved in the United States (US) for treatment of patients aged ≥12 with transfusion-dependent β-thalassemia (TDT). Standard of care (SOC) for TDT includes regular red blood cell transfusions (RBCTs) and iron chelation therapy. This study estimated long-term clinical outcomes and cost-effectiveness of exa-cel vs. SOC among patients with TDT in the US.

Pharmacological reversal of abnormal promoter DNA hypermethylation at tumor suppressor genes (TSGs) is a key therapeutic paradigm for cancer management. However, the clinical efficacy of currently approved nucleoside analog hypomethylating agents (HMAs) is limited by dose-dependent toxicity and high resistance rates. Nonnucleoside, DNA methyltransferase 1 (DNMT1)-selective inhibitors offer a promising alternative. To date, only limited chemotypes, exemplified by the dicyanopyridine derivative GSK3685032 (GSK5032), have demonstrated translatable DNMT1 inhibition, with resistance emerging upon prolonged exposure. To address these limitations, we employ structure-guided scaffold hopping and chemical optimization to develop a series of DNMT1 inhibitors (DNMT1i) featuring a bicyclic 7-azaindole scaffold. We identify DMI46, a potent enzymatic DNMT1i capable of reversing cancer-specific DNA methylation abnormalities and TSG silencing, leading to robust antileukemic effects and favorable tolerability. Cryoelectron microscopy (cryo-EM) studies reveal that the 7-azaindole inhibitor exhibits enhanced intercalation into hemi-methylated CpG dyads and increased minor-groove contacts within the DNMT1/hemimethylated DNA complex compared to GSK5032. These structural features enable sustained DNMT1 targeting and significant antiproliferative activity of DMI46 in GSK5032-resistant acute myeloid leukemia (AML) cells. We also demonstrate DMI46's capacity to overcome AML resistance to nucleoside-based HMAs both in vitro and in vivo. These findings introduce a distinct DNMT1i chemotype with enhanced on-target engagement and broad applicability against HMA-resistant AML.

Microbial-derived short-chain fatty acids regulate a variety of pathways in the healthy colonic mucosa. In particular, butyrate serves as the primary energy source for colonocytes and regulates gene transcription by stabilizing the transcription factor hypoxia-inducible-factors (HIF) and functioning as a histone deacetylase (HDAC) inhibitor. A limitation of butyrate as a therapeutic is its rapid metabolism in differentiated colonocytes. Furthermore, intestinal stem cells (ISCs) respond differently to butyrate, preferentially using glucose for energy procurement. To address these limitations, we explored metabolite mimicry to identify compounds with potent or selective biological responses within the butyrate pathway(s). We found an analog, 3-chlorobutyrate (3-Cl BA), that significantly enhances epithelial barrier formation and wound healing in vitro. Mechanistically, we revealed that 3-Cl BA is a potent HDAC inhibitor. Furthermore, unlike butyrate, 3-Cl BA does not stabilize HIF and it is not used as metabolic fuel. In vivo studies in a dextran sulfate sodium-colitis model revealed that contrary to butyrate, 3-Cl BA is protective. Studies in stem-like colonoids demonstrated that only butyrate inhibits ISC proliferation and differentiation. Furthermore, it was recently reported that HIF stabilization inhibits ISCs activity. Given the fact that butyrate but not 3-Cl BA stabilizes HIF, we surmised that 3-Cl BA would circumvent these detrimental functional consequences. We demonstrate here that pharmacologic HIF stabilization inhibits colonoid differentiation and that genetic loss of HIF significantly promotes ISC differentiation. This study reveals a promising butyrate analog protective in colitis and demonstrates the advantages of metabolite mimicry to dissect selective biological functions from major metabolites in the gut.

Colonic mucus forms a critical barrier to intestinal contents, providing the protection necessary for intestinal and organismal health. The mucus is composed of gel-forming mucin secreted by goblet cells residing in the epithelial layer lining the colon; yet, our knowledge of many of the attributes and functions of mucus and the goblet cells remains limited. A planar array of colonic cryptlike structures with a thick covering of goblet cell-generated mucus was developed to mimic the differentiated colonic epithelium and provide an easily accessible physiologic mucus layer for the evaluation of mucus barrier function in response to intestinal microbiota and toxins. The human microphysiological system (MPS) was created using an impermeable thin film patterned with a geometrical array of a 10 μm × 10 μm scale through holes overlaid with collagen and primary colonic stem cells. The array dimensions, collagen thickness, and growth factor concentration were optimized to assess the cell density, proliferation, migration, differentiation, and mucus thickness. A 175 μm center-to-center distance between the through holes or stem cell niches and a collagen thickness of 10 μm were found to be optimal to enable long-term culture (≥23 days) with a discrete stem/proliferative cell region and a differentiated cell zone enriched in goblet cells and supporting a 250 μm-thick adherent mucus layer. The mucus layer acted as an effective barrier to block the access of the Staphylococcus aureus α-hemolysin toxin to the epithelial cells as well as to protect the cell layer from both Staphylococcus aureus and Lactobacillus rhamnosus. The intestinal mucus MPS will be a useful tool for emulating the intestinal epithelium to study the interplay of stem cell renewal, goblet cell differentiation, mucus dynamics, and microbiota-mucus-host interactions.

Copyright: © 2026 Makovec et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Prostate gland cells can be transcriptionally and morphologically characterized as basal and luminal. About 30–40% of advanced prostate cancers (PC) harbor basal-like transcription programs. In castration-resistant PC (CRPC), studies indicate that basal and stem cell-like (SCL) tumors are major resistance mechanisms to androgen receptor (AR)-targeted therapies. SCL tumors have reduced AR activity and increased stem-cell activity that promotes tumor formation, which contributes to poor clinical outcomes. We determined that CREB5 is a key regulator of basal and SCL transcriptional programs and tumor-forming phenotypes in PC. Through in silico modeling of PC transcriptomes and several pre-defined PC signaling programs, CREB5 expression was best associated with basal-like gene signatures and SCL-associated genes in primary PC and CRPCs (n = 493 and 208). This included associations with FOSL1 and other AP-1 transcription factors. We further found that CREB5 interacted with AP-1 proteins and bound to the regulatory elements of AP-1 genes, suggesting a mechanistic role in regulating the activity of AP-1 genes. In AR-positive cells, CREB5 overexpression promoted cell colony growth with tumorigenic properties and increased tumor size in vivo. These findings implicate CREB5 as a driver of the transcriptional programs underlying AR-independent basal and SCL CRPC subtypes, and this activity is detectable in primary PC.