Biology subjects

Bhamidipati, K.

Publications and source records attributed to Bhamidipati, K..

5 recordsLinked to original sources

bioRxiv2026

Fibroblasts neurotrophin signaling sustains pathological vascular maturation in rheumatoid arthritis.

Treatment failures in rheumatoid arthritis (RA) leads to undesirable morbidity associated with immunosuppression. Recent studies of synovial tissue from refractory RA patients highlight the role of synovial fibroblasts and vascular endothelium in driving treatment failure. Utilizing high-dimensional spatial transcriptomics, we uncovered a crucial role for neurotrophin signaling in driving abnormal vascular maturation in RA synovia. Neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3), induce differentiation of synovial fibroblasts into mural cells - pericytes and vascular smooth muscle cells. Mechanistically, NOTCH3 signaling activates a cascade of neurotrophin signaling through transcriptional induction of NGFR, a co-receptor for NGF. In RA synovial tissue explants, stimulation with NGF, BDNF, or NT3 leads to a dramatic increase in maturation of synovial tissue vasculature. Conversely, pharmacologic inhibition with neurotrophin inhibitors drastically abolished maturation of vascularization in RA synovial explants. Notably, the FDA-approved tropomyosin receptor kinase (TRK) inhibitors larotrectinib and entrectinib effectively reverse synovial vascular maturation in human RA tissue explants.Our findings suggest that fibroblast-derived neurotrophin signaling is a critical pathway in sustaining mature blood vessels in RA synovia, and that neurotrophin inhibitors reverse abnormal vascular maturation in RA. One Sentence SummaryIn rheumatoid arthritis, fibroblast neurotrophin signaling drives abnormal vascular maturation by inducing differentiation of fibroblasts into vascular mural cells.

molecular biology↗

bioRxiv2025

Fibroblasts sense spatial proximity via an EGFR CREB5 axis to restore quiescent synovial lining in remission rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease where the synovial lining membrane undergoes pathological changes resulting in joint destruction. In healthy joints, the synovial lining is essential for joint homeostasis, forming a selective barrier and secreting lubricating molecules, yet the mechanisms that restores homeostatic synovial lining during RA remission remains poorly understood. Here, we applied spatial transcriptomics to examine biopsies of RA patients in remission to identify a mechanism that orchestrates a phenotypic switch specifying synovial quiescent lining fibroblast differentiation. Spatial transcriptomics revealed a proximity-sensing program where at low cell-density, fibroblasts adopt proliferative and fibrotic transcriptional state characterized by expression of MKI67, COL1A2 and COL6A2, whereas at high cell-density, fibroblasts induce a quiescent lining fibroblast transcriptional program characterized by PRG4, CLU and PDPN. Mechanistically, fibroblasts sense spatial proximity through HB-EGF-EGFR signaling, which leads to phosphorylation of transcription factor CREB5. Perturbation of the EGFR-CREB5 axis abolishes fibroblast proximity-sensing and blocks synovial lining fibroblast differentiation. Conversely, EGFR activation by the ligand HB-EGF or pharmacologic activation of CREB5 is sufficient to induce synovial lining fibroblast differentiation. Together, our findings define a novel spatial proximity-sensing pathway underlying a return to homoeostatic fibroblast function during RA remission. By sensing their spatial proximity to neighboring fibroblasts, synovial fibroblasts translate these positional cues into signals that lead to restoration of normal, steady-state synovial lining membrane.

genomics↗

bioRxiv2025

Spatial patterning of fibroblast TGFβ signaling underlies treatment resistance in rheumatoid arthritis

Treatment-refractory rheumatoid arthritis (RA) is a major unmet need, and the mechanisms driving treatment resistance are poorly understood. To identify molecular determinants of RA non-remission, we performed spatial transcriptomic profiling on pre- and post-treatment synovial tissue biopsies from treatment naive patients who received conventional DMARDs or adalimumab for 6 months. In the baseline biopsies of non-remission patients, we identified significant expansion of fibrogenic fibroblasts marked by high expression of COMP, a fibrosis-associated extracellular matrix protein. COMPhi fibroblasts localized to perivascular niches that, unexpectedly, served as transcriptional hubs for TGF{beta} activity. We identified endothelial-derived Notch signaling as an upstream regulator of fibroblast TGF{beta} signaling via its dual role in driving TGF{beta} isoform expression and suppressing TGF{beta} receptors, generating a proximal-distal gradient of TGF{beta} activity. Further, disruption of steady-state Notch signaling in vitro enabled fibrogenic fibroblast activation. Analysis of post-treatment biopsies revealed marked expansion of COMPhi fibroblasts in non-remission RA patients, despite evidence of successful immune cell depletion, suggesting a spatiotemporal process of fibrogenic remodeling linked to treatment resistance. Collectively, our data implicates targeting of TGF{beta} signaling to prevent exuberant synovial tissue fibrosis as a potential therapeutic strategy for refractory RA.

immunology↗

bioRxiv2024

Marginated neutrophils in the lungs effectively compete for nanoparticles targeted to the endothelium, serving as a part of the reticuloendothelial system

Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but has not achieved this goal with the vast majority of targets. One rare example of success in this pursuit has been the 25+ years of studies targeting the lung endothelium using nanoparticles conjugated to antibodies against endothelial surface molecules. However, here we show that such "endothelial-targeted" nanocarriers also effectively target the lungs numerous marginated neutrophils, which reside in the pulmonary capillaries and patrol for pathogens. We show that marginated neutrophils uptake of many of these "endothelial-targeted" nanocarriers is on par with endothelial uptake. This generalizes across diverse nanomaterials and targeting moieties and was even found with physicochemical lung tropism (i.e., without targeting moieties). Further, we observed this in ex vivo human lungs and in vivo healthy mice, with an increase in marginated neutrophil uptake of nanoparticles caused by local or distant inflammation. These findings have implications for nanomedicine development for lung diseases. These data also suggest that marginated neutrophils, especially in the lungs, should be considered a major part of the reticuloendothelial system (RES), with a special role in clearing nanoparticles that adhere to the lumenal surfaces of blood vessels. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/597904v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@17e0518org.highwire.dtl.DTLVardef@809eb6org.highwire.dtl.DTLVardef@33d9a7org.highwire.dtl.DTLVardef@169863_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2021

Human KIR+CD8+ T cells target pathogenic T cells in Celiac disease and are active in autoimmune diseases and COVID-19

Previous reports show that Ly49+CD8+ T cells can suppress autoimmunity in mouse models of autoimmune diseases. Here we find a markedly increased frequency of CD8+ T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalent of the Ly49 family, in the blood and inflamed tissues of various autoimmune diseases. Moreover, KIR+CD8+ T cells can efficiently eliminate pathogenic gliadin-specific CD4+ T cells from Celiac disease (CeD) patients leukocytes in vitro. Furthermore, we observe elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 and influenza-infected patients, and this correlates with disease severity and vasculitis in COVID-19. Expanded KIR+CD8+ T cells from these different diseases display shared phenotypes and similar T cell receptor sequences. These results characterize a regulatory CD8+ T cell subset in humans, broadly active in both autoimmune and infectious diseases, which we hypothesize functions to control self-reactive or otherwise pathogenic T cells. One-Sentence SummaryHere we identified KIR+CD8+ T cells as a regulatory CD8+ T cell subset in humans that suppresses self-reactive or otherwise pathogenic CD4+ T cells.

immunology↗