Search Results (209)

Platelet-rich gel (PRG) is a fibrin-based biobased biomaterial generated by activating platelet-rich plasma (PRP), yet its biological characterization has commonly relied on univariate measurements of isolated mediators. This study aimed to define the multivariate biological organization of PRG and related hemocomponents (PRP, chemically induced platelet lysate (CIPL), and plasma) in a canine model under single exposure to non-steroidal anti-inflammatory drugs (NSAIDs). In a randomized crossover design (n = 6 dogs), hemocomponents were produced at baseline (0 h) and 6 h after administration of carprofen or firocoxib. Platelet and white blood cell (WBC) counts, growth factors (platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor beta-1 (TGF-β1)), and cytokines (tumor necrosis factor alpha (TNF-α), interleukin-1 beta, and interleukin-10) were integrated using linear mixed-effects modeling, principal component analysis (PCA), and hierarchical clustering. PRG was derived from a leukocyte-poor PRP precursor with moderate platelet enrichment (~1.6-fold vs. whole blood) and a marked WBC reduction (~8–9-fold). In mixed-effects modeling, hemocomponent type significantly influenced the PDGF-BB:TNF-α log-ratio, with PRG (estimate −1.12; 95% CI −1.34 to −0.90) and plasma (−2.06; 95% CI −2.28 to −1.84) lower than PRP, while CIPL did not differ. Time and NSAID effects were not supported. PCA identified two orthogonal axes explaining 61.3% of total variance (PC1 = 43.7%, PC2 = 18.6%), separating a platelet/trophic dimension (log(PDGF-BB), log(TGF-β1), platelet count, PDGF-BB:TNF-α log-ratio) from an inflammatory dimension (log(TNF-α), log(IL-1β)). Overall, hemocomponent composition emerged as the primary determinant of mediator organization, supporting the interpretation of PRG as a structured, biomaterial defined by coordinated mediator networks. Full article

We evaluated human embryonic stem cell-derived mesenchymal stem cells (ES-MSCs) on collagen scaffolds for meniscus-like neotissue formation and ex vivo repair of human osteoarthritic (OA) meniscal defects. Collagen type I fibrous scaffolds were pneumatospun, and laminate scaffolds were fabricated from electrospun PLA/collagen; crosslinked; heparin conjugated; fibronectin coated; functionalized with TGFβ1, TGFβ3, or PDGFbb; seeded with ES-MSCs; and cultured for 4 weeks, followed by in vitro assessment or ex vivo implantation into 3.5 mm human meniscus defects for 5 weeks. Pneumatospinning generated highly porous scaffolds that supported uniform cell infiltration, while laminate scaffolds demonstrated interlocking fiber interfaces and enhanced mechanical properties. TGFβ1 and TGFβ3 immobilization enhanced scaffold bioactivity, defined as growth factor-mediated increases in meniscus-like matrix deposition, collagen fiber organization, and meniscogenic gene expression, by significantly increasing safranin O staining, collagen type II deposition, collagen fiber polarization, and ACAN expression. TGFβ3 additionally increased COL1A1 expression and pushout shear modulus; TGFβ1 increased peak pushout stress, indicating superior ex vivo mechanical integration. Laminate scaffolds resulted in extensive cell infiltration, robust neotissue formation (elastic modulus ~2.4 MPa), and improved ex vivo tissue integration when functionalized with TGFβ3. The data indicated that ES-MSC-seeded, heparin-conjugated, TGFβ-immobilized pneumatospun/electrospun collagen–PLA scaffolds support meniscogenic differentiation and biomechanical integration, with repair of focal meniscal defects and potential for partial meniscus replacement. Full article

Background: Sirtuin 3 (SIRT3), a mitochondrial NAD⁺-dependent deacetylase, plays a central role in regulating mitochondrial metabolism, oxidative stress, and cell survival. Although SIRT3 has been implicated in angiogenesis, apoptosis, and inflammation, its global proteomic impact on the brain remains unclear. This study aimed to systematically characterize alterations in angiogenesis-, apoptosis-, chemokine-, and cytokine-related proteins in the brains of SIRT3 knockout (SIRT3 KO aka SIRT3⁻/⁻) mice compared with wild-type (WT) controls. Methods: Adult male C57BL/6 WT and SIRT3 KO mice were analyzed using proteome profiler antibody microarrays covering 53 angiogenesis factors, 21 apoptosis markers, 28 chemokines, and 111 cytokines. Protein expression changes were quantified by chemiluminescence imaging and densitometric analysis. Results: The results showed a distinct suppression of angiogenic proteins (amphiregulin, angiogenin, DPPIV, GM-CSF, IGFBP-2, IGFBP-3, IL-1β, PDGF-AA, PDGF-BB, proliferin, serpin F1, thrombospeondin-2, TIMP-4, and VEGF-B), activation of both pro-apoptotic (BAD, cytochrome c, Smac/DIABLO, HIF-1α, Fas, TNF R1, and TRAILR2) and anti-apoptotic, stress-related proteins (Bcl-x, catalase, HO/HMOX2, HSP27, HSP70, and MCL1) in the SIRT3 KO animals compared with the WT controls. Notably, SIRT3 deficiency was associated with increased expression of inflammatory mediators linked to glial activation and neurodegeneration (BLC/CCL13, LIX/CXCL5, MIG/CXCL9, chitinase 3-like 1, CCL22/MDC, IL-6, myeloperoxidase, osteopontin, RBP4, Reg3G, and TNF-α), alongside disturbed proteins involved in immune surveillance and vascular remodeling (6Ckine/CCL21, chemerin, DF, EGF, fractalkine/CX3CL1, HGF, IGFBP-6, IL-16, and I-TAC). Conclusions: Collectively, these findings demonstrate that SIRT3 is a key regulator of mitochondrial-dependent vascular, apoptotic, and neuroimmune pathways in the brain, and that its loss creates a molecular environment consistent with heightened vulnerability to neurodegenerative processes. Full article

Background and Objectives: Soft tissue regeneration in oral surgery has undergone remarkable progress in the last decade, supported by the development of innovative laser technologies, advanced biomaterials, platelet-rich plasma (PRP), mesenchymal stem cells (MSCs), and three-dimensional (3D) printing. Lasers are increasingly used not only for incision and coagulation but also for photobiomodulation, promoting cellular proliferation, angiogenesis, and tissue healing. The purpose of this review is to analyze the current advances in soft tissue regeneration, with a particular focus on the clinical use of lasers and their integration with other regenerative strategies. In parallel, hard tissue regeneration has evolved through the synergistic use of bioactive scaffolds, recombinant human growth factors (rhBMP-2, rhPDGF-BB), MSCs, and 3D-printed constructs. These innovations have enhanced alveolar bone regeneration, implant osseointegration, and periodontal tissue repair, offering predictable clinical outcomes. Materials and Methods: A review of the literature published between 2015 and 2025 was conducted through PubMed, Scopus, Web of Science, Embase, and Google Scholar. Clinical and preclinical studies on the use of CO₂, Nd:YAG, Er:YAG, diode, and 445 nm lasers, biomaterials, PRP, MSCs, growth factors, and 3D-printed scaffolds were included. Results: Laser applications demonstrated significant benefits in epithelialization, biostimulation, and reduction in postoperative discomfort in soft tissues. For hard tissues, the combined use of MSCs, bioactive scaffolds, and growth factors promoted osteogenic differentiation, bone volume preservation, and improved mechanical stability. Photobiomodulation enhanced osteoblastic activity and accelerated bone remodeling, while 3D-printed scaffolds provided personalized architecture for optimal integration. Conclusions: Regenerative approaches integrating lasers, biomaterials, PRP, MSCs, growth factors, and 3D printing represent safe, minimally invasive, and effective strategies for the regeneration of both soft and hard oral tissues. These multidisciplinary techniques improve healing quality, functional recovery, and esthetic outcomes, reflecting the growing trend toward precision and technology-driven regenerative oral surgery. Full article

During tendon healing, collagen III expression precedes that of collagen I. The collagen I-to-III ratio at a certain time point post-laceration serves as an indicator of the healing status. Consequently, it is crucial to understand how different therapeutic approaches to support tendon healing affect the collagen I-to-III ratio in the extracellular matrix of a healing tendon, particularly across distinct anatomical zones. We compared the impact of a platelet-derived growth factor-BB (PDGF-BB) treatment via controlled release from coaxially electrospun DegraPol^® (Ab medica, Cerro Maggiore, Italy) hollow-fiber mesh with a treatment by the vehicle alone (no PDGF-BB) in the rabbit Achilles tendon full transection model and provide data on the collagen I-to-III ratio 3 weeks post-operation. For this purpose, we compared a dual-color Herovici staining to two single IHC labeling, for collagen I and collagen III, respectively. Herovici staining (HV) was expected to offer a more precise approach (pink-to-blue histogram) than the two separately labeled IHC stainings, both with chromogenic DAB labeling (red-to-green histogram), despite an anticipated positive correlation of the data assessed by these methods. Different zones were compared, i.e., native tendon tissue, reactive zone at interface to implant, hot zone within the core of the healing tendon and the zone within the scaffold, meaning the collagen deposited within the fibers of the implanted DegraPol^® tube, respectively. The analysis revealed that the ratios obtained via HV correlated weakly with the ratios obtained by IHC. Based on HV, PDGF-BB therapy led to higher collagen I-to-III ratios in all zones, except for the zone within the scaffold pores, while IHC did not reveal significant differences. Notably, collagen I-to-III ratios were not higher in immediate proximity, but rather distal from the PDGF-BB releasing implant, specifically in the core of the healing tendon tissue. Hence, a PDGF-BB therapy is suggestive of greater collagen maturation in specific zones of the healing tendon. Full article

In individuals with diabetes, dysregulation of inflammatory processes hinders the progression of wounds into the proliferative phase, resulting in chronic, non-healing wounds. Total saponins from Rhizoma Panacis majoris (SRPM), bioactive compounds naturally extracted from the rhizome of Panax japonicus C.A.Mey. var. major (Burk.) C.Y.Wu and K.M.Feng, have demonstrated extensive anti-inflammatory and immunomodulatory properties. This study aims to elucidate the molecular mechanisms underlying the facilitative effects of SRPM on diabetic wound healing, with particular emphasis on its anti-inflammatory actions. A high-fat diet combined with streptozotocin (STZ) administration was used to induce type 2 diabetes in rats. After two weeks of oral treatment with SRPM suspension, a wound model was established. Subsequently, a two-week course of combined local and systemic therapy was administered using both SRPM suspension and SRPM gel. SRPM markedly reduces the levels of pro-inflammatory mediators, including IL-1α, IL-1β, IL-6, MIP-1α, TNF-α, and MCP-1, in both rat tissues and serum. Concurrently, it increases the expression of anti-inflammatory cytokines such as IL-10, TGF-β1, and PDGF-BB, while also enhancing the expression of the tissue remodelling marker bFGF. Additionally, SRPM significantly decreases the accumulation of apoptotic cells within tissues by downregulating the pro-apoptotic gene Caspase-3, upregulating the anti-apoptotic gene Bcl-2, and increasing the expression of the apoptotic cell clearance receptor MerTK. Moreover, SRPM inhibits neutrophil infiltration and the release of neutrophil extracellular traps (NETs) in tissues, promotes macrophage polarisation towards the M2 phenotype, and activates the Wnt/β-catenin signalling pathway at the molecular level. SRPM promotes the healing of wounds in diabetic rats potentially due to its anti-inflammatory properties. Full article

TIGIT and its ligand CD155 (PVR) are emerging immune checkpoints in colorectal cancer (CRC), but their associations with mutational subtypes and the tumor immune milieu remain unclear. We quantified TIGIT and CD155 proteins by ELISA in paired CRC tumors and matched surgical margins (n = 131) and evaluated associations with clinicopathological features, MSI status, and KRAS/NRAS/BRAF/PIK3CA/AKT1 mutations (n = 104). Both TIGIT and CD155 were significantly elevated in tumor tissue versus margins (p < 0.0001) and showed no association with TNM stage, clinical stage, grade, or tumor location. TIGIT levels were higher in MSI than MSS tumors and in BRAF-mutant compared to BRAF wild-type tumors, while CD155 expression showed no consistent MSI- or mutation-dependent differences. Cytokine profiling identified IFN-g as the only shared positive associate of TIGIT and CD155; CD155 additionally associated with TRAIL, IL-1Ra, M-CSF, and PDGF-bb. In external transcriptomic validation (TCGA-CRC), GSEA indicated enrichment of interferon/inflammatory programs in TIGIT-high tumors, while CD155-high tumors preferentially showed proliferation-related MYC/E2F/G2M signatures. Together, these findings support tumor-wide upregulation of the TIGIT/CD155 axis in CRC and suggest that TIGIT, more than CD155, tracks with MSI/BRAF-associated immune activation, providing a rationale for patient stratification in checkpoint-directed immunotherapy. Full article

Background/Objectives: Platelet-rich plasma (PRP) is increasingly used in musculoskeletal medicine. Variability in PRP composition, driven by preparation- and donor-related factors, is considered a major contributor to inconsistent clinical outcomes. This study investigated whether habitual dietary patterns are associated with the cellular and molecular composition of leukocyte-poor PRP (LP-PRP). Methods: In this cross-sectional study, 75 healthy adults (25 vegans, 25 vegetarians, and 25 omnivores) who adhered to their dietary patterns for ≥6 months were enrolled. LP-PRP was prepared by a standardized protocol. Cell profiles were quantified in whole blood and LP-PRP; LP-PRP proteins (IL-6, IGF-1, HGF, and PDGF-BB) were measured by ELISA. Group differences, correlations, and multivariable regressions were performed. Results: Whole blood differed by diet with respect to total leukocytes, lymphocytes, and basophils, while platelet and erythrocyte counts did not. In LP-PRP, platelet enrichment ratios and leukocyte counts were comparable across diets. IL-6 in LP-PRP was lower in vegans vs. omnivores (p = 0.017); the Animal-Based Diet Score correlated positively with LP-PRP IL-6 and remained independently associated in regression (β = 0.35, p = 0.004). While IGF-1, HGF, and PDGF-BB did not differ between dietary groups, intake-based analyses revealed associations between specific dietary components and LP-PRP proteins; notably, the fruit and vegetable intake correlated inversely with PDGF-BB, and platelet–growth factor coupling was most pronounced among omnivores. Conclusions: Dietary patterns were associated with selected molecular components of LP-PRP—most consistently IL-6—while cell counts remain largely unchanged. However, interventional studies are needed to establish causality and determine whether dietary modification can influence clinical outcomes. Full article

HIV infection is accompanied by production of pro-inflammatory cytokines, which are regarded as critical in neuronal damage, leading to brain dysfunction. To develop diagnostic tools and therapeutic interventions, we need to measure CNS response to immune activation, hence the need to identify specific cytokine biomarkers that are associated with brain damage in HIV infection. This cross-sectional retrospective study applied Magnetic Resonance Imaging (MRI) for brain volumetric measurements and high-throughput Luminex-based immunoassays to quantify plasma cytokine and chemokine concentrations. We then used generalized linear models and Partial Least Square Regression models to evaluate the association between brain volume and plasma cytokines in predominantly treatment-naïve participants with HIV. After adjusting for clinical and demographic variables, we observed that higher MCP-1 (p = 0.013) and RANTES (p = 0.002) remained significantly associated with lower cortical white matter volume, whereas the anti-inflammatory cytokine IL-9 (p = 0.025) and the growth factors PDGFBB (p = 0.012) and VEGF (p = 0.001) were associated with higher cortical white matter volume. Only IL-6 (p = 0.010) was significantly associated with lower subcortical grey matter volume. Higher concentrations of five pro-inflammatory cytokines, IL-6 (p = 0.0001), IL-8 (p = 0.018), GCSF (p = 0.004), MCP-1 (p = 0.004), and RANTES (p = 0.015), were associated with lower total grey matter volume. Associations of pro-inflammatory cytokines with lower brain volume could imply a link to mechanisms of HIV-associated brain damage, which may lead to neurocognitive impairment. Therefore, the use of highly sensitive neuroimaging and high-throughput immunoassays in HIV-associated brain disorders has potential applications in clinical assessments and therapeutic monitoring. Full article

Background: Chronic cutaneous wounds such as diabetic foot ulcers, venous leg ulcers, pressure injuries, and burns remain a global clinical burden. These wounds are often arrested in inflammatory or ischemic stages due to impaired angiogenesis and growth factor deficiencies. Biologic therapies, such as platelet-rich plasma (PRP) and recombinant growth factors, aim to restore these deficits and accelerate repair. Methods: A narrative review of PubMed and Google Scholar (2015–2025) identified 64 English-language studies, including randomized controlled trials, meta-analyses, and translational investigations evaluating PRP and recombinant growth factors in wound healing. Results: Randomized trials and meta-analyses show that adjunctive autologous PRP increases complete wound closure versus standard care in chronic ulcers, including diabetic foot and venous leg ulcers (odds ratios ≈ 2–8), and improves healing rates in pressure injuries (odds ratio ≈ 3.4), without increasing adverse events. In diabetic foot ulcers, PDGF-BB and EGF, together with PRP, consistently improve complete healing and reduce ulcer area. In burns, topical EGF and bFGF shorten healing time by ~3 days in superficial partial-thickness wounds and by >5 days in deeper burns, with generally improved scar outcomes. Conclusions: PRP offers broad, autologous biologic activation, while recombinant growth factors deliver high-potency, targeted precision. Together, they represent complementary regenerative strategies that can shorten healing times and improve outcomes in chronic wounds. Standardized multicenter trials quantifying cytokine composition, cost-effectiveness, and long-term limb-salvage benefit are warranted to guide their integration into routine clinical practice. Full article

Alzheimer’s Disease (AD) management is challenging due to limitations in detection methods. Currently, cerebrospinal fluid (CSF) biomarkers involve assessing β-amyloid (Aβ) and phosphorylated tau proteins. The lumbar puncture procedure to obtain CSF is invasive and sometimes causes significant anxiety in patients. In contrast, plasma biomarkers would allow rapid, accurate, and cost-effective diagnosis, while minimizing invasiveness and discomfort. Using a dataset involving 120 plasma proteins from clinically diagnosed AD patients versus cognitively normal subjects, we developed classification models by applying various machine learning algorithms (EBlasso, EBEN, XGBoost, LightGBM, TabNet, and TabPFN) to plasma proteomic measurements. Gene ontology and pathway enrichment, and a literature review were used to evaluate the potential relevance of the biomarkers identified in AD-related mechanisms. Biomarkers identified were also evaluated for the enrichment of aging-related biomarkers. The models developed yielded high AUROC and accuracy, mostly >0.9. Proteins selected as predictors by all the models included Angiopoietin-2 (ANG-2), epidermal growth factor (EGF), Interleukin 1α (IL-1α), and platelet growth factor subunit B (PDGF-BB). Ample previous literature supported their relevance in AD. The pool of all the biomarkers identified was significantly enriched with known aging-related biomarkers (p = 0.040). Applying cutting-edge algorithms is expected to be advantageous for developing AD prediction models with plasma proteomic data, and future large studies to externally validate the constructed models in other populations to assess their generalizability is important. The proteins uncovered may represent novel preventative or therapeutic targets. Full article

Background: Alveolar bone resorption remains a major challenge in implant and prosthetic rehabilitation. While autologous bone grafts are still considered the gold standard, their biological and surgical limitations have promoted the use of synthetic biomaterials such as biphasic calcium phosphate (BCP), β-tricalcium phosphate (β-TCP), nanocrystalline hydroxyapatite, and bioactive glass. Methods: This systematic review, conducted in accordance with PRISMA guidelines, was based on a comprehensive search performed in March 2025 across PubMed, MEDLINE, Embase, and Google Scholar. A total of 11 clinical studies—including both randomized and non-randomized comparative trials—were identified. Due to the marked heterogeneity of study designs and outcome measures, meta-analysis was not feasible. Reported outcomes focused on bone volume preservation, residual biomaterial, implant stability, histological integration, and postoperative complications. Results: Overall, synthetic biomaterials achieved satisfactory bone regeneration and implant stability, with mean bone preservation ranging between 85% and 95%, often comparable to xenografts and other grafting materials. Among the materials analyzed, β-TCP and BCP generally demonstrated superior resorption control and dimensional stability, while bioactive glass showed favorable integration and remodeling rates. The addition of bioactive agents such as rhBMP-2, rhPDGF-BB, or platelet-rich plasma further enhanced new bone formation. Conclusions: Within the limits of current evidence, synthetic biomaterials show clinical performance comparable to xenografts, particularly in socket preservation and ridge augmentation procedures. Their predictable handling, absence of donor-site morbidity, and potential for bioactive enhancement make them valuable tools for routine clinical use. Larger, standardized trials with long-term follow-up are needed to validate these findings and refine material selection in alveolar bone regeneration. Full article

Deep venous thrombosis (DVT) is characterized by the formation of a thrombus within deep veins. The unmet need to identify new biomarkers and causal risk factors in DVT patients has led to the use of novel techniques, such as metabolite analyses. This study aimed to characterize metabolic alterations in acute DVT patients using ¹H-NMR spectroscopy and determine the persistence of these changes over a six-month follow-up. Metabolomics, particularly ¹H-NMR spectroscopy, was performed on serum samples from acute DVT patients (first 30 days from diagnosis) and healthy controls (HC). Additionally, 10 plasma markers were evaluated using a Luminex kit. A total of 30 patients, with a mean age of 44 ± 12.5 years, primarily women (9 males:21 females), were included. Acute DVT patients showed elevated inflammatory markers, such as IL-6, IL-8, PDGF-AB/BB, and P-selectin, which later decreased in the follow-up group. However, adhesion molecules like sVCAM-1 and sICAM-1 have increased after six months. Metabolomics analysis revealed significantly decreased levels of glutamine, glucose, and branched-chain amino acids (BCAAs), alongside increased lactate levels in acute DVT samples. Metabolomic profiles showed only partial normalization at follow-up, indicating persistent metabolic dysregulation. Overall, the reduced glucose metabolism and increased lactate levels indicate anaerobic metabolism, likely caused by tissue hypoxia due to impaired blood flow. Glutamine, essential for DNA, ATP, and protein synthesis, was notably reduced, potentially impairing endothelial cell proliferation and vascular repair. The presence of adhesion molecules in the follow-up group confirms persistent endothelial dysfunction. These findings suggest that metabolic and endothelial alterations may persist long after acute inflammation resolves in DVT patients. In conclusion, the persistence of metabolic dysregulation suggests chronic metabolic stress in these patients, potentially resulting from ongoing endothelial damage, low-grade inflammation, or altered mitochondrial function due to past tissue hypoxia. Full article

Collagen is widely used in tissue engineering due to its excellent biocompatibility; however, its limited intrinsic mechanical strength restricts its application in load-bearing environments. This study introduces dialdehyde starch (DAS) as a biocompatible macromolecular cross-linker to enhance the mechanical integrity of collagen hydrogels. Collagen gels were cross-linked with DAS during neutralization under optimized conditions, resulting in a significant increase in compressive stiffness (up to ~125 kPa), thereby improving their suitability for mechanically demanding applications. Degradation studies of DAS-crosslinked collagen confirmed the long-term stability of the gel, while post-neutralization heparin incorporation improved bifunctionality, as evidenced by increased surface retention. FT-IR analysis confirmed the successful DAS cross-linking and heparin conjugation while preserving the native collagen structure. Bioactivity assays of DAS-crosslinked and heparin-conjugated collagen gel demonstrated enhanced chondrocyte migration in PDGF-BB-functionalized gels and improved cell viability, proliferation, and matrix deposition in TGF-β3-treated constructs. Preliminary ex vivo culture using a rabbit osteochondral defect model showed promising tissue integration and glycosaminoglycan accumulation. These results highlight the potential of DAS-crosslinked and heparin-conjugated collagen hydrogels as mechanically robust and biologically supportive scaffolds for osteochondral tissue engineering and regenerative medicine applications. Full article

Pathological vascular remodeling—central to restenosis, atherosclerosis, and vasculo-proliferative diseases—depends on the phenotypic switching of vascular smooth muscle cells (VSMCs) from a quiescent, contractile state to a synthetic, proliferative program. Although the receptor tyrosine kinase c-Kit is implicated in proliferation, migration, and tissue repair, its role in VSMC plasticity has yet to be fully understood. Using c-Kit haploinsufficient mice subjected to right carotid artery ligation (CAL) and primary aortic VSMC cultures, we show that c-Kit is required for the contractile-to-synthetic transition. In vitro, c-Kit haploinsufficiency halved c-Kit expression, reduced 5-bromo-2′-deoxyuridine (BrdU) incorporation, and blunted platelet-derived growth factor BB (PDGF-BB)-induced repression of contractile genes. c-Kit–deficient VSMCs exhibited a senescence program with increased p16^INK4a/p21 expression and upregulated senescence-associated secretory phenotype (SASP) mediators. RNA-Seq of carotid arteries 7 days post-ligation revealed that wild-type arteries activated cell-cycle pathways and suppressed contractile signatures, whereas c-Kit-deficient carotid arteries failed to fully engage proliferative programs and instead maintained contractile gene expression. At 28 days post CAL in vivo, c-Kit haploinsufficiency produced markedly reduced neointima, fewer Ki67+ VSMCs, more p16^INK4a+ cells, and impaired re-endothelialization. Because progenitor-to-VSMC differentiation contributes to remodeling, we tested adult cardiac stem/progenitor cells (CSCs) as a model system of adult progenitor differentiation. Wild-type CSCs efficiently generated induced VSMCs (iVSMCs) with appropriate smooth-muscle gene upregulation; c-Kit–deficient rarely did so. Restoring c-Kit with a BAC transgene rescued both the smooth-muscle differentiation and proliferative competence of c-Kit-deficient iVSMCs. Collectively, our data identified c-Kit as a gatekeeper of reparative VSMC plasticity. Adequate c-Kit enables progenitor-to-VSMC commitment and the expansion of newly formed VSMCs while permitting injury-induced proliferation and matrix synthesis; reduced c-Kit locks cells in a hypercontractile, senescence-prone state and limits neointima formation. Modulating the c-Kit axis may therefore offer a strategy to fine-tune vascular repair while mitigating pathological remodeling. Full article