Biology subjects

Wikenheiser-Brokamp, K. A.

Publications and source records attributed to Wikenheiser-Brokamp, K. A..

5 recordsLinked to original sources

bioRxiv2025

MYD88 mutations in clonal hematopoiesis promote inflammation and hematopoietic stem cell expansion

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by expansion of mutant hematopoietic stem and progenitor cells (HSPCs) and an increased risk of chronic diseases and cancers. While mutations in DNMT3A, TET2, and ASXL1 are common in CHIP, the contribution of less frequent gene mutations is not well understood. Here, we report MYD88 mutations, including lymphoma-associated and novel variants in blood cells of the general population and newly diagnosed solid cancer patients. MYD88 CHIP mutations in HSPCs activate NF-{kappa}B, indicating a gain-of-function activity. Modeling MYD88 CHIP in mice, Myd88L252P (equivalent of human L265P) expression resulted in a competitive fitness advantage of HSPCs. Myd88L252P HSPCs exhibit a myeloid cell bias and inflammation, leading to hematologic disease. Single-cell RNA sequencing indicated that Myd88L252P expands distinct hematopoietic and immune cell clusters and activates immune-related pathways in HSPCs. An IRAK1/4 inhibitor suppressed MYD88-dependent NF-{kappa}B activation and reversed Myd88L252P cell expansion. Overall, MYD88 mutations contribute to CHIP by inducing innate immune pathways in HSPCs and inflammatory disease.

cancer biology↗

bioRxiv2023

Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis

The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored the mechanisms of silica-induced pulmonary fibrosis in a mouse model using multiple modalities including wholelung single-nucleus RNA sequencing. These analyses revealed that in addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor-{kappa}B ligand (RANKL) in pulmonary lymphocytes and alveolar type II cells. Furthermore, anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated silica-induced pulmonary fibrosis. We conclude that silica induces osteoclast-like differentiation of distinct recruited and tissue resident monocyte populations, leading to progressive lung injury, likely due to sustained elaboration of bone resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis. One Sentence SummarySilica induces the alveolar epithelium to reprogram recruited and resident pulmonary myeloid cells to become osteoclasts that contribute to pulmonary fibrosis.

pathology↗

bioRxiv2022

Guided construction of single cell reference for human and mouse lung

Accurate cell type identification is a key and rate-limiting step in single cell data analysis. Single cell references with comprehensive cell types, reproducible and functional validated cell identities, and common nomenclatures are much needed by the research community to optimize automated cell type annotation and facilitate data integration, sharing, and collaboration. In the present study, we developed a novel computational pipeline to utilize the LungMAP CellCards as a dictionary to consolidate single-cell transcriptomic datasets of 104 human lungs and 17 mouse lung samples and constructed "LungMAP CellRef" and "LungMAP CellRef Seed" for both normal human and mouse lungs. "CellRef Seed" has an equivalent prediction power and produces consistent cell annotation as does "CellRef" but improves computational efficiency and simplifies its utilization for fast automated cell type annotation and online visualization. This atlas set incorporates 48 human and 40 mouse well-defined lung cell types catalogued from diverse anatomic locations and developmental time points. Using independent datasets, we demonstrated the utility of our CellRefs for automated cell type annotation analysis of both normal and disease lungs. User-friendly web interfaces were developed to support easy access and maximal utilization of the LungMAP CellRefs. LungMAP CellRefs are freely available to the pulmonary research community through fast interactive web interfaces to facilitate hypothesis generation, research discovery, and identification of cell type alterations in disease conditions.

bioinformatics↗

bioRxiv2021

Novel insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis.

Pulmonary alveolar microlithiasis (PAM) is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a PAM lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes suggested a role for osteoclast-like cells in the defense against microliths. While investigating the mechanisms of microlith clearance, we found that Npt2b modulates pulmonary phosphate homeostasis through effects on alternative phosphate transporter activity and alveolar osteoprotegerin, and that microliths induce osteoclast formation and activity in a receptor activator of nuclear factor-{kappa}B ligand (RANKL) and dietary phosphate dependent manner. This work reveals that Npt2b and pulmonary osteoclast-like cells play key roles in pulmonary homeostasis and suggest potential new therapeutic targets for the treatment of lung disease.

molecular biology↗

bioRxiv2019

Identification of the lymphangioleiomyomatosis cell and its uterine origin

Lymphangioleiomyomatosis (LAM) is a metastasizing neoplasm of reproductive age women that causes cystic lung remodeling and progressive respiratory failure. The source of LAM cells that invade the lung and the reasons that LAM targets women have remained elusive. We employed single cell and single nuclei RNA sequencing on LAM lesions within explanted LAM lungs, known to contain smooth muscle like cells bearing mTOR activating mutations in TSC1 or TSC2, and identified a unique population of cells that were readily distinguished from those of endogenous lung cells. LAMCORE cells shared closest transcriptomic similarity to normal uterus and neural crest. Immunofluorescence microscopy demonstrated the expression of LAMCORE cell signature genes within LAM lesions in both lung and uterus. Serum aptamer proteomics and ELISA identified biomarkers predicted to be secreted by LAMCORE cells. Single cell transcriptomics strongly supports a uterine neural crest origin of LAMCORE cells; providing insights into disease pathogenesis and informing future treatment strategies for LAM.\n\nSIGNIFICANCEPresent study identified a novel population of LAMCORE cells, which is likely originated from uterine neural crest; identified novel LAM cell-specific secretome proteins that hold promise as potential biomarkers and therapeutic targets. Advancing the understanding of LAM pathogenesis and metastasis model may yield broader insights into the biology of cancer.

cancer biology↗