Biology subjects

Jamora, C.

Publications and source records attributed to Jamora, C..

16 recordsLinked to original sources

bioRxiv2026

Actin-dependent mechanotransduction controls nucleocytoplasmic partitioning of DNMT3a through ERK1/2 signaling during cutaneous wound healing

Cutaneous wound healing is a multifaceted physiological process that requires a cell state transition from homeostasis to tissue repair. An important contributor to this reprogramming is the wound-induced mechanical cues that are perceived by epidermal keratinocytes. Previously we identified that the nuclear translocation of the de novo DNA methyltransferase 3A (DNMT3a) upon wounding as an important regulator of this cell-state transition. However, the molecular mechanisms linking mechanotransduction to epigenetic regulation remain incompletely understood. Here we show that under homeostasis, active ERK1/2 phosphorylates DNMT3a, intramolecularly masking its nuclear localization signal (NLS), resulting in its cytoplasmic sequestration. Upon wounding actin cytoskeleton remodeling leads to the downregulation of the Extracellular Signal-Related Kinase 1/2 (ERK 1/2) pathway. Wound-induced ERK1/2 inactivation unmasks the NLS, enabling DNMT3a nuclear translocation. Collectively, these findings define a mechanotransduction-driven signaling axis linking cytoskeletal dynamics to epigenetic regulation and confirms an active role for differentiated keratinocytes in initiating early wound repair programs.

cell biology↗

bioRxiv2025

Mindin-α-M-Integrin endocytosis activates STAT3 to maintain keratinocyte stemness

Signalling networks rely not only on specific protein interactions but also on the subcellular locales at which these occur. Such spatial control is fundamental to cellular behaviour in both physiological and pathological scenarios. In studying keratinocyte stemness, we previously identified a Mindin-M{beta}2 (CD11b/CD18) interaction that triggers STAT3 activation. Here, we delineate the mechanism underlying this response and show that the F-Spondin domain of Mindin constitutes the minimal integrin-binding module required to initiate downstream signalling. F-Spondin binding to the integrin at the plasma membrane does not elicit the full activation state of the integrin. Instead, it promotes Src-kinase dependent endocytosis of the integrin receptor to the early endosomes. Analysis of integrin conformational dynamics reveals that this compartmental shift is essential as the acidic environment of early endosomes drives the transition into a signalling-competent state. This mechanism extends to pathological contexts, as we demonstrate a requirement for endocytosis in activating STAT3 signalling and preserving stem-like properties in a cancer stem cell model. Together, these findings highlight a previously unrecognized layer of spatial control in integrin signalling, confirming endosomal trafficking as a critical determinant of stem cell behaviour and offering new conceptual and therapeutic opportunities across regenerative biology and cancer.

cell biology↗

bioRxiv2025

12-Hydroxystearic acid induces epidermal keratinocytes to secrete antimicrobial peptides that are potent inhibitors of viral infection.

Epidermal keratinocytes produce antimicrobial peptides (AMPs) that serve as a crucial component of the skins innate immune barrier. These peptides effectively target a broad spectrum of pathogenic microorganisms while preserving commensal microbiota essential for skin barrier homeostasis and overall skin health. Regulating the release of these AMPs presents a promising approach to enhancing the skin barriers defense mechanisms with minimal side effects. We have identified 12-hydroxystearic acid (12-HSA) as a potent stimulator of AMP secretion from primary epidermal keratinocytes. Mechanistic investigations revealed that, akin to bacterial stimulation, 12-HSA induces AMP release through the downregulation of caspase-8, which subsequently activates the inflammasome. Notably, we discovered that 12-HSA mediates caspase-8 downregulation via the acute activation of DNA methyltransferase 3A (DNMT3A), leading to transcriptional silencing of the caspase-8 locus. Importantly, 12-HSA is widely utilized in the cosmetic industry for its several skin beneficial properties including hydration and emolliency. Our findings suggest that this compound can be leveraged to enhance innate immune defenses in the skin, effectively mobilizing stored AMPs from keratinocytes to counteract microbial threats. This discovery highlights the potential for 12-HSA as a novel agent in dermatological applications aimed at fortifying skin barrier immunity.

cell biology↗

bioRxiv2024

Poly (A) Binding Protein 2 is critical for stem-progenitor differentiation during regeneration in the planarian Schmidtea mediterranea.

Post-transcriptional regulation has emerged as a key mechanism to regulate stem cell renewal and differentiation, which is essential for understanding tissue regeneration and homeostasis. Poly(A)-binding proteins are a family of RNA-binding proteins that play a vital role in post-transcriptional regulation by controlling mRNA stability and protein synthesis. The involvement of poly(A) binding proteins in a wide range of cellular functions is increasingly being investigated. In this study, we used the regenerative model organism planarian Schmidtea mediterranea, to demonstrate the critical role of poly(A)-binding protein 2 (PABP2) in regulating neoblast maintenance and differentiation. A deficit in PABP2 blocks the transition of neoblasts towards immediate early progenitors, leading to an enhanced pool of non-committed neoblasts and a decreased progenitor population. This is reflected in variations in the transcriptome profile, providing evidence of downregulation in multiple lineages. Thus, insufficiency of PABP2 resulted in defective formation and organization of tissue leading to abnormal regeneration. Our study reveals the essential role of PABP2 in regulating genes that mediate stem cell commitment to early progenitors during tissue regeneration.

cell biology↗

bioRxiv2024

Evaluation of melanocyte stem cell population in vitiliginous skin pre- and post-narrow-band UVB phototherapy

Vitiligo vulgaris is an autoimmune disorder characterized by the destruction of epidermal melanocytes leading to white lesions devoid of pigmentation. The destruction of epidermal melanocytes. Is driven by tissue-resident and circulatory immune cells that maintain an inflammatory milieu. Two percent of the global population suffer from vitiligo vulgaris, of which, prevalence is higher in the Indian population. Narrow-band UV-B (NBUVB) phototherapy is commonly used as an economical, non-invasive, and well-tolerated treatment modality. NBUVB promotes the migration of melanocyte stem cells (MelSC) to the epidermis, thus regaining pigmentation in affected individuals. Despite the widespread use of NBUVB in secondary and tertiary clinics in India, the status of melanocyte stem cells and immune cells, pre-and post-NBUVB is not well understood. We observe that following NBUVB phototherapy, melanocyte stem cells (pax3+) re-populate the epidermis and express melanogenesis markers (Tyrosinase, Trp2, kit) concomitant with a decrease in CD3+ T-cells within the skin. Our study reaffirms the therapeutic efficacy of NBUVB in promoting re-pigmentation in an Indian cohort of vitiligo patients. Further, NBUVB is effective in reducing overall immune load, widely considered a major contributor to the pathogenesis of the disease.

cell biology↗

bioRxiv2024

Dermal wound healing contribution of aqueous extracts of Acalypha indica, Calotropis gigantea, Bacopa monnieri and their combination

Wound healing is a complex process that requires a well-orchestrated integration of an array of molecular events such as cell migration and proliferation, deposition and remodeling of extracellular matrix components for restoring the structural and functional integrity of the tissue injured. Ayurveda suggests wound healing herbs can achieve enhanced therapeutic effect with reduced toxicity when they are optimally combined in a specific ratio as polyherbal formulation (PHF). The present study was aimed to evaluate the combinatorial wound healing efficacy (in vivo wound closure and histological changes) of aqueous extracts of three medicinal plants (Bacopa monnieri, Acalypha indica and Calotropis gigantea). This study also explored how the combination influenced the overall quality of healed wound. Individual wound closure kinetic performance of aqueous plant extracts in C57B/6J mice was assessed using safe concentrations obtained from human adult dermal fibroblast viability assay. The aqueous plant extract combination optimized using response surface methodology was tested for in vivo wound closure effectiveness. Quality of healed wound was assessed via Hematoxylin & Eosin and immunohistochemical staining of markers (K1, K5, Loricrin, Ki67, CD31 and collagen1). The combination treatment (B.monnieri-15g/ml, A.indica-11.59g/ml, C.gigantea-1g/ml) contributed to faster wound closure (11 days), improved collagen type I remodeling and angiogenesis, complete re-epithelialization, similar epidermal differentiation pattern as that of individual and control treatments. Ki67 staining revealed no significant increase in cell proliferation in combination compared to individual and control. Findings from the study validates the polyherbal combinations impressive capability to promote wound healing.

cell biology↗

bioRxiv2023

Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

Vasculopathy is a common hallmark of various fibrotic disorders including systemic sclerosis (SSc), yet its underlying etiology and contribution to fibrogenesis remain ill-defined. In SSc the vasculopathy typically precedes the onset of fibrosis and we observed that this phenomenon is recapitulated in the Snail transgenic mouse model of SSc. The vascular anomalies manifest as deformed vessels, endothelial cell dysfunction and vascular leakage. Our investigation into the underlying mechanism of this phenotype revealed that Angiopoietin-like protein 2 (Angptl2), secreted by the Snail transgenic keratinocytes, is a principal driver of fibrotic vasculopathy. In endothelial cells, Angptl2 upregulates pro-fibrotic genes, downregulates the tight junction protein Claudin 5, and prompts the acquisition of mesenchymal characteristics. Inhibiting endothelial cell junctional instability and consequently vascular leakage with a synthetic analog of the microbial metabolite Urolithin A (UAS03) effectively mitigated the vasculopathy and inhibited fibrogenesis. Thus, Angptl2 emerges as a promising early biomarker of the disease and inhibiting the vasculopathy inducing effects of this protein with agents such as UAS03 presents an appealing therapeutic avenue to reduce disease severity. These insights hold the potential to revolutionize the approach to the treatment of fibrotic diseases by targeting the vascular defects.

pathology↗

bioRxiv2023

Partial alopecia area retains bulge hair follicle progenitor cells in Indian androgenetic alopecia patients

Androgenic alopecia (AGA) is a pathological condition characterized by the progressive decrease of scalp hair follicle density. Completely bald areas of AGA scalp still retain hair follicle stem cells but the progenitor cells are drastically decreased in number. However, it is unknown when the progenitor cells begin to diminish in number during the progression of AGA. Despite the prevalence of AGA in 58% of the Indian male population, no study to date has characterized the hair follicle stem and progenitor cell populations in AGA patients in this ethnic group. We observed that the partially bald area retains progenitor cells expressing CD34 and Sox9 but they are not present in the hair follicles in the completely bald area. Our study sheds light on the timeframe for effective therapeutic interventions based on modulating regulatory mechanisms to reinitiate the existing inactive follicle stem cells.

pathology↗

bioRxiv2023

Bacopa monnieri phytochemicals regulate fibroblast cell migration via modulation of focal adhesions

The Bacopa monnieri plant contains a large repertoire of active phytochemicals that have been used extensively in traditional medicine for the treatment of various complex diseases. More recently it has been shown to increase the wound healing rate in rats, though its mechanism of action is largely unknown. Here we investigated the cellular pathways activated by a methanol extract of Bacopa monnieri in human dermal fibroblasts, which play many critical roles in the wound healing program. Gene expression analysis revealed that Bacopa monnieri extract can enhance tissue repair by modulating multiple processes involved in the wound healing program such as migration, proliferation, and angiogenesis. We discovered that Bacopa monnieri extract can increase migration of fibroblasts via modulating the size and number of focal adhesions. Bacopa monnieri-mediated changes in focal adhesions are dependent on 5{beta}1 integrin activation and subsequent phosphorylation of Focal Adhesion Kinase (FAK). Altogether our results suggest that Bacopa monnieri extract could enhance the wound healing rate via modulating fibroblast migration in the wound bed.

cell biology↗

bioRxiv2022

Niacinamide enhances cathelicidin mediated SARS-CoV-2 membrane disruption

The continual emergence of new SARS-CoV-2 variants threatens the effectiveness of worldwide vaccination programs and highlights the need for complementary strategies for a sustainable containment plan. A promising approach is to mobilize the bodys own antimicrobial peptides (AMPs), to combat SARS-CoV-2 infection and propagation. We have found that human cathelicidin (LL37), an AMP found at epithelial barriers as well as in various bodily fluids, has the capacity to neutralise multiple strains of SARS-CoV-2. Biophysical and computational studies indicate that LL37s mechanism of action is through the disruption of the viral membrane. This antiviral activity of LL37 is enhanced by the hydrotropic action of niacinamide, which may increase the bioavailability of the AMP. Interestingly, we observed inverse correlation between LL37 levels and disease severity of COVID-19 positive patients, suggesting enhancement of AMP response would be an effective therapeutic avenue to mitigate disease severity and overcome vaccine escape.

pathology↗

bioRxiv2022

Mindin differentially regulates fibroblast subpopulations via distinct members of the Src family kinases during fibrogenesis.

Fibrosis is the result of excessive deposition of extracellular matrix (ECM) proteins leading to tissue hardening and loss of organ function. A central player driving fibrosis is the activated fibroblast, which exhibits enhanced migration, proliferation, contraction, and ECM production. However, this raises an interesting puzzle of whether the same fibroblast performs all of the processes that fall under the umbrella term of "activation". Given the heterogeneity of fibroblasts in connective tissues, there are subpopulations of fibroblasts that perform specific functions that are under different regulatory controls. Using a transgenic mouse model of skin fibrosis, we find that the secretion of Mindin from Snail transgenic keratinocytes differentially alters the characteristic of distinct fibroblast subpopulations. Mindin induces migration and inflammatory gene expression of the Sca1+ subpopulation of dermal fibroblasts in a Fyn kinase-dependent manner. On the other hand, Mindin increases the contractile behaviour and collagen production in the papillary CD26+ dermal fibroblasts via c-Src. Moreover, in the context of the fibrotic microenvironment of the tumour stroma, we found that differential responses of resident fibroblasts subpopulations to Mindin extend to the generation of functionally heterogeneous cancer-associated fibroblasts (CAFs). Overall, this work highlights the importance of Mindin in mediating the cellular and signalling heterogeneity of dermal fibroblasts in skin fibrosis and cancer.

cell biology↗

bioRxiv2022

Mindin is essential for cutaneous fibrogenesis in a new mouse model of systemic sclerosis

Fibrosis is a result of chronically activated fibroblasts leading to the overproduction of extracellular matrix (ECM), causing tissue hardening and loss of organ function. Systemic sclerosis (SSc) is a fibrotic skin disease marked by inflammation, autoimmunity and vasculopathy along with progressive fibrosis of the skin and internal organs. A major bottleneck in understanding the etiology of SSc has been the lack of a holistic animal model that can mimic the human SSc disease. We found that the transcription factor Snail is overexpressed in the epidermis of SSc patients and a transgenic mouse recapitulating this expression pattern is sufficient to induce hallmark clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin in fibrogenesis. Mindin is produced by Snail transgenic skin keratinocytes and aids fibrogenesis by inducing inflammatory cytokine and collagen production in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis.

pathology↗

bioRxiv2021

The initiation of the wound healing program is regulated by the convergence of mechanical and epigenetic cues

Wound healing in the skin is a complex physiological process that is a product of a cell state transition from homeostasis to repair. Mechanical cues are increasingly being recognized as important regulators of cellular reprogramming, but the mechanism by which it is translated to changes in gene expression and ultimately cellular behavior remains largely a mystery. To probe the molecular underpinnings of this phenomenon further, we used the downregulation of caspase-8 as a biomarker of a cell entering the wound-healing program. We found that the wound-induced release of tension within the epidermis leads to the alteration of gene expression via the nuclear translocation of the DNA methyltransferase 3A (DNMT3a). This enzyme then methylates promoters of genes that are known to be downregulated in response to wound stimuli as well as potentially novel players in the repair program. Overall, these findings illuminate the convergence of mechanical and epigenetic signaling modules that are important regulators of the transcriptome landscape required to initiate the tissue repair process in the differentiated layers of the epidermis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/463764v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1b5b182org.highwire.dtl.DTLVardef@198e646org.highwire.dtl.DTLVardef@1361f4forg.highwire.dtl.DTLVardef@418a84_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

Snail maintains the stem/progenitor state of skin epithelial cells and carcinomas through the autocrine effect of the matricellular protein Mindin

Intratumoral heterogeneity poses a major challenge in designing effective anti-cancer strategies. Accumulating evidence suggests that this heterogeneity arises from cancer stem cells (CSCs) that also drives tumor aggressiveness and drug resistance. The stemness of CSCs are preserved by an ill-defined combination of intrinsic and external factors and is particularly intriguing since they exist within a sea of similar cells at various degrees of differentiation. In models of cutaneous squamous cell carcinoma (cSCC), we discovered a non-EMT function for the transcription factor Snail in maintaining stemness of keratinocytes. This is accomplished by the secretion of the matricellular protein Mindin from Snail expressing cells, which creates a protective niche that impedes differentiation. In an autocrine fashion, extracellular Mindin activates a Src -STAT3 pathway to reinforce the stem/progenitor phenotype and disruption of this signalling module in human cSCC attenuates tumorigenesis. The expression of Mindin in multiple carcinomas, and its critical role in cancer progression suggests that it would be a promising target for therapeutic intervention.

cell biology↗

bioRxiv2020

Mechanical Instability of Adherens Junctions Overrides Intrinsic Quiescence of Hair Follicle Stem Cells

Vinculin, a mechanotransducer associated with both adherens junctions (AJ) and focal adhesions (FA) plays a central role in force transmission through these cell-cell and cell-substratum contacts. Here we describe the conditional knock out (KO) of vinculin in murine skin. Remarkably, we find that the loss of vinculin function results in the loss of bulge stem cell (BuSC) quiescence. We demonstrate that vinculin KO cells are impaired in force generation resulting in mechanically weak AJs. Mechanistically, vinculin functions by keeping -catenin in a stretched conformation, which in turn regulates the retention of YAP1, another potent mechanotransducer and regulator of cell proliferation, to the junctions. Conditional KO of -catenin specifically in the BuSCs further corroborates the importance of stable AJs in the maintenance of quiescence and stemness. Altogether, our data provides definitive mechanistic insights into the hitherto unexplored regulatory link between the mechanical stability of cell-junctions and the maintenance of BuSC quiescence.

cell biology↗

bioRxiv2019

Extracellular Caspase-1 regulates migration of hair follicle stem cells upon wounding

The wound-healing process is a paradigm of the directed migration of various pools of stem cells from their niche to the site of injury where they replenish damaged cells. Two decades have elapsed since the observation that wounding activates multipotent hair follicle stem cells to infiltrate the epidermis, but the cues that coax these cells out of their niche remains unknown. Using an excisional wound and genetic mouse models of wound healing, we discovered that Caspase-1, a protein classically known as an integral component of the cytosolic inflammasome, is secreted and has a non-canonical role in the extracellular milieu. Through its Caspase Activation Recruitment Domain (CARD), Caspase-1 is sufficient to initiate chemotaxis of hair follicle stem cells into the epidermis. Uncovering this novel function of Caspase-1 also facilitates a deeper understanding of the mechanistic basis of the epithelial hyperplasia found to accompany numerous inflammatory skin diseases.

cell biology↗