Inamul Kabir - Academia.edu (original) (raw)

Papers by Inamul Kabir

Nature Communications, 2021

During lung fibrosis, the epithelium induces signaling to underlying mesenchyme to generate exces... more During lung fibrosis, the epithelium induces signaling to underlying mesenchyme to generate excess myofibroblasts and extracellular matrix; herein, we focus on signaling in the mesenchyme. Our studies indicate that platelet-derived growth factor receptor (PDGFR)-β+ cells are the predominant source of myofibroblasts and Kruppel-like factor (KLF) 4 is upregulated in PDGFR-β+ cells, inducing TGFβ pathway signaling and fibrosis. In fibrotic lung patches, KLF4 is down-regulated, suggesting KLF4 levels decrease as PDGFR-β+ cells transition into myofibroblasts. In contrast to PDGFR-β+ cells, KLF4 reduction in α-smooth muscle actin (SMA)+ cells non-cell autonomously exacerbates lung fibrosis by inducing macrophage accumulation and pro-fibrotic effects of PDGFR-β+ cells via a Forkhead box M1 to C-C chemokine ligand 2—receptor 2 pathway. Taken together, in the context of lung fibrosis, our results indicate that KLF4 plays opposing roles in PDGFR-β+ cells and SMA+ cells and highlight the impor...

Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth... more Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cells (SMCs) 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 aging induces SMC polyclonality and worsens atherosclerosis through non-cell autonomous effects of aged bone marrow-derived cells. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin β3 resulting in increased cytokine (e.g., tumor necrosis factor [TNF]-α) signaling. In turn, TNFα induces recruitment and expansion of multiple SMCs into the atherosclerotic plaque. Recent studies demonstrate that normal aging is characterized by somatic mutations and clonal expansion of epithelial cells of diverse tissues (e.g., esophagus, endometrium, skin); extrapolating beyond atherogenesis, our results call for future studies evaluating the role of aged myeloid cel...

Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth... more Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cells (SMCs) 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 aging induces SMC polyclonality and worsens atherosclerosis through non-cell autonomous effects of aged bone marrow-derived cells. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin β3 resulting in increased cytokine (e.g., tumor necrosis factor [TNF]-α) signaling. In turn, TNFα induces recruitment and expansion of multiple SMCs into the atherosclerotic plaque. Recent studies demonstrate that normal aging is characterized by somatic mutations and clonal expansion of epithelial cells of diverse tissues (e.g., esophagus, endometrium, skin); extrapolating beyond atherogenesis, our results call for future studies evaluating the role of aged myeloid cel...

In simple terms, the cardiovascular system consists of a sophisticated pump (i.e., the heart) and... more In simple terms, the cardiovascular system consists of a sophisticated pump (i.e., the heart) and a remarkable array of tubes (i.e., the blood and lymphatic vessels). Arteries and arterioles (the efferent blood vessels in relation to the heart) deliver oxygen, nutrients, paracrine hormones, blood and immune cells, and many other products to the capillaries, small-caliber, thin-walled vascular tubes. These substances are then transported through the capillary wall into the extravascular tissues, where they participate in critical physiological processes. In turn, waste products are transported from the extravascular space back into the blood capillaries and returned by the venules and veins (the afferent vessels) to the heart. Alternatively, approximately 10% of the fluid returned to the heart courses via the lymphatic system to the large veins. To develop normally, the embryo requires the delivery of nutrients and removal of waste products beginning early in development, and, indeed...

Nature Aging

Cellular senescence and smooth muscle cells are key features of the atherosclerotic plaque; howev... more Cellular senescence and smooth muscle cells are key features of the atherosclerotic plaque; however, how senescent cells regulate smooth muscle cells is largely unknown. Herein, a new study in Nature Aging illuminates this interplay, providing insights into plaque dynamics and stability with potentially profound implications for heart attack and stroke.

Cell Death & Disease

Serine palmitoyltransferase (SPT) is the rate-limiting enzyme for sphingolipid biosynthesis. SPT ... more Serine palmitoyltransferase (SPT) is the rate-limiting enzyme for sphingolipid biosynthesis. SPT has two major subunits, SPTLC1 and SPTLC2. We previously found that liver Sptlc2 deficiency in early life impairs the development of adherens junctions. Here, we investigated the role of Sptlc2 deficiency in intestine. We treated Sptlc2-Flox/villin-Cre-ER T2 mice with tamoxifen (days 1, 2, and 3) to ablate Sptlc2 specifically in the intestine. At day 6 after tamoxifen treatment, Sptlc2deficient mice had significantly decreased body weight with concurrent diarrhea and rectal bleeding. The number of goblet cells was reduced in both large and small intestine of Sptlc2-deficient mice compared with controls. Sptlc2 deficiency suppressed the level of mucin2 in the colon and increased circulating lipopolysaccharides, suggesting that SPT activity has a housekeeping function in the intestine. All Sptlc2-deficient mice died 7-10 days after tamoxifen treatment. Notably, supplementation with antibiotics and dexamethasone reduced lethality by 70%. We also found that colon specimens from patients with inflammatory bowel diseases had significantly reduced Sptlc2 expression, SPTLC2 staining, and goblet cell numbers. SPT activity is crucial for intestinal cell survival and barrier function.

Nature Communications, 2021

During lung fibrosis, the epithelium induces signaling to underlying mesenchyme to generate exces... more During lung fibrosis, the epithelium induces signaling to underlying mesenchyme to generate excess myofibroblasts and extracellular matrix; herein, we focus on signaling in the mesenchyme. Our studies indicate that platelet-derived growth factor receptor (PDGFR)-β+ cells are the predominant source of myofibroblasts and Kruppel-like factor (KLF) 4 is upregulated in PDGFR-β+ cells, inducing TGFβ pathway signaling and fibrosis. In fibrotic lung patches, KLF4 is down-regulated, suggesting KLF4 levels decrease as PDGFR-β+ cells transition into myofibroblasts. In contrast to PDGFR-β+ cells, KLF4 reduction in α-smooth muscle actin (SMA)+ cells non-cell autonomously exacerbates lung fibrosis by inducing macrophage accumulation and pro-fibrotic effects of PDGFR-β+ cells via a Forkhead box M1 to C-C chemokine ligand 2—receptor 2 pathway. Taken together, in the context of lung fibrosis, our results indicate that KLF4 plays opposing roles in PDGFR-β+ cells and SMA+ cells and highlight the impor...

Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth... more Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cells (SMCs) 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 aging induces SMC polyclonality and worsens atherosclerosis through non-cell autonomous effects of aged bone marrow-derived cells. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin β3 resulting in increased cytokine (e.g., tumor necrosis factor [TNF]-α) signaling. In turn, TNFα induces recruitment and expansion of multiple SMCs into the atherosclerotic plaque. Recent studies demonstrate that normal aging is characterized by somatic mutations and clonal expansion of epithelial cells of diverse tissues (e.g., esophagus, endometrium, skin); extrapolating beyond atherogenesis, our results call for future studies evaluating the role of aged myeloid cel...

Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth... more Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cells (SMCs) 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 aging induces SMC polyclonality and worsens atherosclerosis through non-cell autonomous effects of aged bone marrow-derived cells. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin β3 resulting in increased cytokine (e.g., tumor necrosis factor [TNF]-α) signaling. In turn, TNFα induces recruitment and expansion of multiple SMCs into the atherosclerotic plaque. Recent studies demonstrate that normal aging is characterized by somatic mutations and clonal expansion of epithelial cells of diverse tissues (e.g., esophagus, endometrium, skin); extrapolating beyond atherogenesis, our results call for future studies evaluating the role of aged myeloid cel...

In simple terms, the cardiovascular system consists of a sophisticated pump (i.e., the heart) and... more In simple terms, the cardiovascular system consists of a sophisticated pump (i.e., the heart) and a remarkable array of tubes (i.e., the blood and lymphatic vessels). Arteries and arterioles (the efferent blood vessels in relation to the heart) deliver oxygen, nutrients, paracrine hormones, blood and immune cells, and many other products to the capillaries, small-caliber, thin-walled vascular tubes. These substances are then transported through the capillary wall into the extravascular tissues, where they participate in critical physiological processes. In turn, waste products are transported from the extravascular space back into the blood capillaries and returned by the venules and veins (the afferent vessels) to the heart. Alternatively, approximately 10% of the fluid returned to the heart courses via the lymphatic system to the large veins. To develop normally, the embryo requires the delivery of nutrients and removal of waste products beginning early in development, and, indeed...

Nature Aging

Cellular senescence and smooth muscle cells are key features of the atherosclerotic plaque; howev... more Cellular senescence and smooth muscle cells are key features of the atherosclerotic plaque; however, how senescent cells regulate smooth muscle cells is largely unknown. Herein, a new study in Nature Aging illuminates this interplay, providing insights into plaque dynamics and stability with potentially profound implications for heart attack and stroke.

Cell Death & Disease

Serine palmitoyltransferase (SPT) is the rate-limiting enzyme for sphingolipid biosynthesis. SPT ... more Serine palmitoyltransferase (SPT) is the rate-limiting enzyme for sphingolipid biosynthesis. SPT has two major subunits, SPTLC1 and SPTLC2. We previously found that liver Sptlc2 deficiency in early life impairs the development of adherens junctions. Here, we investigated the role of Sptlc2 deficiency in intestine. We treated Sptlc2-Flox/villin-Cre-ER T2 mice with tamoxifen (days 1, 2, and 3) to ablate Sptlc2 specifically in the intestine. At day 6 after tamoxifen treatment, Sptlc2deficient mice had significantly decreased body weight with concurrent diarrhea and rectal bleeding. The number of goblet cells was reduced in both large and small intestine of Sptlc2-deficient mice compared with controls. Sptlc2 deficiency suppressed the level of mucin2 in the colon and increased circulating lipopolysaccharides, suggesting that SPT activity has a housekeeping function in the intestine. All Sptlc2-deficient mice died 7-10 days after tamoxifen treatment. Notably, supplementation with antibiotics and dexamethasone reduced lethality by 70%. We also found that colon specimens from patients with inflammatory bowel diseases had significantly reduced Sptlc2 expression, SPTLC2 staining, and goblet cell numbers. SPT activity is crucial for intestinal cell survival and barrier function.