Biology subjects

Cheong, J.-G.

Publications and source records attributed to Cheong, J.-G..

4 recordsLinked to original sources

bioRxiv2024

Semaphorin 4A maintains functional diversity of the hematopoietic stem cell pool

Somatic stem cell pools are comprised of diverse, highly specialized subsets whose individual contribution is critical for the overall regenerative function. In the bone marrow, myeloid-biased HSC (myHSC) are indispensable for replenishment of myeloid cells and platelets during inflammatory response but at the same time, become irreversibly damaged during inflammation and aging. Here, we identify an extrinsic factor, Semaphorin 4A (Sema4A), which non cell-autonomously confers myHSC resilience to inflammatory stress. We show that the absence of Sema4A, myHSC inflammatory hyper-responsiveness in young mice drives excessive myHSC expansion, myeloid bias and profound loss of regenerative function with age. Mechanistically, Sema4A is mainly produced by neutrophils, signals via a cell surface receptor Plexin D1 and safeguards myHSC epigenetic state. Our study shows that by selectively protecting a distinct stem cell subset, an extrinsic factor preserves functional diversity of somatic stem cell pool throughout organismal lifespan.

cell biology↗

bioRxiv2024

High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils

High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1 in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1 in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in [~]50% of treated hosts. Hence, neutrophil-intrinsic IRE1 facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.

immunology↗

bioRxiv2023

Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection.

Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic potential and wide-ranging impact on global health. Here, we investigated epigenetic imprinting across cell lineages in a disease relevant murine model of SARS-CoV-2 recovery. Past SARS-CoV-2 infection resulted in increased chromatin accessibility of type I interferon (IFN-I) related transcription factors in airway-resident macrophages. Mechanistically, establishment of this innate immune memory required viral pattern recognition and canonical IFN-I signaling and augmented secondary antiviral responses. Past SARS-CoV-2 infection ameliorated disease caused by the heterologous respiratory pathogen influenza A virus. Insights into innate immune memory and how it affects subsequent infections with heterologous pathogens to influence disease pathology could facilitate the development of broadly effective therapeutic strategies.

immunology↗

bioRxiv2023

A hematopoietic stem cell subset that retains memory of prior inflammatory stress accumulates in aging and clonal hematopoiesis

Inflammation activates many blood cell types, driving aging and malignancy. Yet, hematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long blood production. To understand HSC adaptation to inflammation, we developed xenograft inflammation-recovery models and performed single cell multiomics on isolated human HSC. Two transcriptionally and epigenetically distinct HSC subsets expressing canonical HSC programs were identified. Only one showed sustained transcriptional and epigenetic changes after recovery from inflammatory treatments. This HSC inflammatory memory (HSC-iM) program is enriched in memory T cells and HSCs from recovered COVID-19 patients. Importantly, HSC-iM accumulates with age and with clonal hematopoiesis. Overall, heritable molecular alterations in a subset of human HSCs, an adaptation to long-term inflammatory stress, may predispose to heightened age-related risk of blood cancer and infection. One-Sentence SummaryInflammation across a lifetime rewires human HSCs to produce a distinct HSC subset with both beneficial and deleterious fitness consequences.

cell biology↗