Biology subjects

Phan, Q.

Publications and source records attributed to Phan, Q..

4 recordsLinked to original sources

bioRxiv2026

Cbfb2 gene dosage programs the differential lymphoid lineage developmental potential of fetal and adult hematopoietic progenitors

Innate-like lymphocyte subsets are generated predominantly during early-life windows, yet the mechanisms that restrict their development in adulthood remain unclear. Here we identify Cbfb2 gene dosage as a quantitative regulator of stage-specific lymphoid potential. We show that reduction of CBF{beta}2 levels unlocks fetal-like competence in adult hematopoietic progenitors, enabling robust generation of IL-17-producing {gamma}{delta} T (T{gamma}{delta}17) cells. Although Cbfb2 haploinsufficiency minimally alters steady-state transcription, chromatin profiling of H3K4me3 revealed promoter-level changes in adult lymphoid-primed multipotent progenitors consistent with altered developmental priming. In adult bone marrow chimeras, Cbfb+/2m progenitors efficiently generated functional V{gamma}2+ T{gamma}{delta}17 cells in lymph nodes and skin, and restoring Cbfb2 expression suppressed this capacity, establishing a dosage-dependent mechanism. Using an optimized in utero transplantation system, we further demonstrate that fetal niches amplify this latent competence and selectively favor IL-17-committed {gamma}{delta} T cell differentiation over conventional {beta} T cell output. Notch1 haploinsufficiency enhanced T{gamma}{delta}17 generation and phenocopied the effect of CBF{beta}2 dosage reduction, linking quantitative NOTCH1 signaling to innate-like lymphocyte developmental programming. Together, these findings reveal that fetal versus adult lymphopoiesis is governed by quantitative tuning of RUNX:CBF{beta} activity and uncover unexpected plasticity in adult hematopoiesis controlled by transcription factor dosage.

immunology↗

bioRxiv2023

Transcriptional heterogeneity in diabetic foot wounds

Wound repair requires the coordination of multiple cell types including immune cells and tissue resident cells to coordinate healing and return of tissue function. Diabetic foot ulceration is a type of chronic wound that impacts over 4 million patients in the US and over 7 million worldwide (Edmonds et al., 2021). Yet, the cellular and molecular mechanisms that go awry in these wounds are not fully understood. Here, by profiling chronic foot ulcers from non-diabetic (NDFUs) and diabetic (DFUs) patients using single-cell RNA sequencing, we find that DFUs display transcription changes that implicate reduced keratinocyte differentiation, altered fibroblast function and lineages, and defects in macrophage metabolism, inflammation, and ECM production compared to NDFUs. Furthermore, analysis of cellular interactions reveals major alterations in several signaling pathways that are altered in DFUs. These data provide a view of the mechanisms by which diabetes alters healing of foot ulcers and may provide therapeutic avenues for DFU treatments.

cell biology↗

bioRxiv2023

Apoptosis recognition receptors regulate skin tissue repair in mice

Apoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which recognition and clearance of apoptotic cells regulate repair are not fully understood. Here, we use single-cell RNA sequencing to provide a map of the cellular dynamics during early inflammation in mouse skin wounds. We find that apoptotic pathways and efferocytosis receptors are elevated in fibroblasts and immune cells, including resident Lyve1+ macrophages, during inflammation. Interestingly, human diabetic foot wounds upregulate mRNAs for apoptotic genes and display increased and altered efferocytosis signaling via the receptor Axl. During early inflammation in mouse wounds, we detect upregulation of Axl in dendritic cells and fibroblasts via TLR3-independent mechanisms. Inhibition studies in vivo in mice reveal that Axl signaling is required for wound repair but is dispensable for efferocytosis. By contrast, inhibition of another efferocytosis receptor, Timd4, in mouse wounds decreases efferocytosis and abrogates wound repair. These data highlight the distinct mechanisms by which apoptotic cell detection coordinates tissue repair and provides potential therapeutic targets for chronic wounds in diabetic patients.

cell biology↗

bioRxiv2018

Activation of the epidermal growth factor receptor initiates innate immune responses during oropharyngeal candidiasis

During oropharyngeal candidiasis (OPC), Candida albicans invades and damages oral epithelial cells, which respond by producing proinflammatory mediators that recruit phagocytes to foci of infection. The ephrin type-A receptor 2 (EphA2) detects {beta}-glucan and plays a central role in stimulating epithelial cells to release proinflammatory mediators during OPC. The epidermal growth factor receptor (EGFR) also interacts with C. albicans and is known to be activated by the Als3 adhesin/invasin and the Ece1/Candidalysin pore-forming toxin. Here, we investigated the interactions among EphA2, EGFR, Als3 and Ece1/Candidalysin during OPC. We found that Als3 and Ece1/Candidalysin function in the same pathway to damage epithelial cells in vitro. They also work together to cause OPC in mice. EGFR and EphA2 constitutively associate with each other as part of a physical complex and are mutually dependent for C. albicans-induced activation. In vitro, either Als3 or Ece1/Candidalysin is required for C. albicans to activate EGFR, sustain EphA2 activation, and stimulate epithelial cells to secrete CXCL8/IL-8 and CCL20. In the mouse model of OPC, Ece1/Candidalysin alone activates EGFR and induces CXCL1/KC and CCL20 production. Ece1/Candidalysin is also necessary for the production of IL-1 and IL-17A independently of Als3 and EGFR. These results delineate the complex interplay between host cell receptors and C. albicans virulence factors during the induction of OPC and the resulting oral inflammatory response. Author summaryOropharyngeal candidiasis occurs when the fungus Candida albicans proliferates in the mouth. The disease is characterized by fungal invasion of the superficial epithelium and a localized inflammatory response. Two C. albicans virulence factors contribute to the pathogenesis of OPC, Als3 which enables the organisms to adhere to and invade host cells and Ece1/Candidalysin which is pore-forming toxin that damages host cells. Two epithelial cell receptors, ephrin type-A receptor 2 (EphA2) and the epidermal growth factor receptor (EGFR) are activated by C. albicans. Here, we show that EphA2 and EGFR form part of complex and that each receptor is required to activate the other. Als3 and Ece1/Candidalysin function in the same pathway to damage epithelial cells. In isolated epithelial cells, both of these virulence factors activate EphA2 and EGFR, and stimulate the production of inflammatory mediators. In the mouse model of OPC, Ece1/Candidalysin elicits of a subset of the oral inflammatory response. Of the cytokines and chemokines induced by this toxin, some require the activation of EGFR while others are induced independently of EGFR. This work provides a deeper understanding of the interactions among C. albicans virulence factors and host cell receptors during OPC.

microbiology↗