Biology subjects

Kabir, I.

Publications and source records attributed to Kabir, I..

3 recordsLinked to original sources

bioRxiv2024

Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization

Defective elastin and smooth muscle cell (SMC) accumulation characterize both arterial diseases (e.g., atherosclerosis, restenosis and supravalvular aortic stenosis [SVAS]), and physiological ductus arteriosus (DA) closure. Elastin deficiency induces SMC hyperproliferation; however, mechanisms underlying this effect are not well elucidated. Elastin (ELN) is expressed from embryonic day (E) 14 in the mouse aorta. Immunostains of Eln(+/+) and Eln(-/-) aortas indicate that SMCs of the Eln null aorta are first hyperproliferative at E15.5, prior to morphological differences. Bulk RNA-seq reveals that sphingosine kinase 1 (Sphk1) is the most upregulated transcript in Eln(-/-) aortic SMCs at E15.5. Reduced ELN increases levels of transcription factor early growth response 1 (EGR1), resulting in increased SPHK1 levels in cultured human aortic SMCs and in the mouse aorta at E15.5 and P0.5. Aortic tissue from Williams-Beuren Syndrome patients, who have elastin insufficiency and SVAS, also has upregulated SPHK1 expression. SMC-specific Sphk1 deletion or pharmacological inhibition of SPHK1 attenuates SMC proliferation and mitigates aortic disease, leading to extended survival of Eln(-/-) mice. In addition, EGR1 and SPHK1 are increased in the wild-type mouse DA compared to adjacent descending aorta. Treatment with a SPHK1 inhibitor attenuates SMC proliferation and reduces SMC accumulation, leading to DA patency. In sum, SPHK1 is a key node in elastin deficiency-induced hypermuscularization, and inhibiting this kinase may be a therapeutic strategy for SVAS and select congenital heart diseases in which a patent DA maintains circulation. One Sentence SummarySphingosine kinase 1-induced by defective elastin promotes muscularization in pathological aortic stenosis and physiological ductus arteriosus occlusion.

developmental biology↗

bioRxiv2023

Dedifferentiated early postnatal lung myofibroblasts redifferentiate in adult disease

Alveolarization ensures sufficient lung surface area for gas exchange, and during bulk alveolarization in mice (postnatal day [P] 4.5-14.5), alpha-smooth muscle actin (SMA)+ myofibroblasts accumulate, secrete elastin, and lay down alveolar septae. Herein, we delineate the dynamics of the lineage of early postnatal SMA+ myofibroblasts during and after bulk alveolarization and in response to lung injury. SMA+ lung myofibroblasts first appear at [~]P2.5 and proliferate robustly. Lineage tracing shows that, at P14.5 and over the next few days, the vast majority of SMA+ myofibroblasts downregulate smooth muscle cell markers and undergo apoptosis. Of note, [~]8% of these dedifferentiated cells and another [~]1% of SMA+ myofibroblasts persist to adulthood. Single cell RNA sequencing analysis of the persistent SMA- cells and SMA+ myofibroblasts in the adult lung reveals distinct gene expression profiles. For instance, dedifferentiated SMA- cells exhibit higher levels of tissue remodeling genes. Most interestingly, these dedifferentiated early postnatal myofibroblasts re-express SMA upon exposure of the adult lung to hypoxia or the pro-fibrotic drug bleomycin. However, unlike during alveolarization, these cells that re-express SMA do not proliferate with hypoxia. In sum, dedifferentiated early postnatal myofibroblasts are a previously undescribed cell type in the adult lung and redifferentiate in response to injury.

developmental biology↗

bioRxiv2022

Bone marrow age dictates clonality of smooth muscle-derived cells in the atherosclerotic plaque

Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cell (SMC) progenitors clonally expand giving rise to up to [~]70% of atherosclerotic plaque cells; however, the effect of age on SMC clonality is not known. Our results indicate that aged bone marrow (BM)-derived cells non-cell autonomously induce SMC polyclonality and worsen atherosclerosis. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin {beta}3 resulting in increased tumor necrosis factor [TNF]- signaling. In turn, TNF signals through TNF receptor 1 on SMCs to promote proliferation and induces recruitment and expansion of multiple SMC progenitors into the atherosclerotic plaque. Notably, integrin {beta}3 overexpression in aged BM preserves dominance of the lineage of a single SMC progenitor and attenuates plaque burden. Our results demonstrate a molecular mechanism of aged macrophage-induced SMC polyclonality and atherogenesis and suggest novel therapeutic strategies. Graphical abstractAge of BM-derived monocytes/macrophages determines clonality of SMC lineage in the atherosclerotic plaque. Atherogenesis is depicted in a young (a) or aged (b) host. Aged monocytes/macrophages have decreased levels of the epigenetic regulator TET2, leading to reduction of the 5-hydroxymethylcytosine (5hmC) mark on the Itgb3 promoter. The resulting low integrin {beta}3 levels in aged monocytes/macrophages induces high TNF- levels, facilitating recruitment and expansion of multiple SMC progenitors (polyclonality) in the atherosclerotic plaque and worse disease burden. In contrast, the young control is characterized by mono/oligoclonal SMC expansion in a smaller plaque. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/476756v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@12f7090org.highwire.dtl.DTLVardef@186ff92org.highwire.dtl.DTLVardef@1f4da69org.highwire.dtl.DTLVardef@2f509c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗