Biology subjects

Chavan, A. R.

Publications and source records attributed to Chavan, A. R..

5 recordsLinked to original sources

bioRxiv2026

Non-cell-autonomous removal of protein aggregates via trogocytosis

Protein aggregate formation can cause cell damage and contribute to tissue pathologies including neurodegeneration. Protein aggregates are normally eliminated by cell-intrinsic mechanisms of lysosomal (autophagic) degradation. However, degradative capacity varies between cell types, raising the possibility that high-capacity cell types, such as macrophages, may contribute to aggregate disposal from the low-capacity cells. Here, we show that cellular protein aggregates are removed by macrophages via trogocytosis -- a partial engulfment of the target cells. Lysosomal stress upon protein aggregate accumulation promotes cell surface expression of the transmembrane isoform of the macrophage growth factor CSF1 (tmCSF1), which is detected by macrophages through the CSF1 receptor to drive trogocytosis. Insufficient or impaired degradation of protein aggregates in lysosomes results in their transport along microtubules to the plasma membrane where they physically associate with tmCSF1. This enables macrophages to specifically trogocytose protein aggregates. These findings reveal a protein homeostasis system that eliminates protein aggregates in a non-cell-autonomous manner.

cell biology↗

bioRxiv2026

Heme orchestrates a tissue stress response to proteolytic damage

Whereas cellular stress responses are well defined, tissue-level stress remains poorly understood. Proteases are among the most widespread enzymes, and excessive proteolytic activity drives diseases such as arthritis and chronic obstructive pulmonary disease, yet unifying features of this stress are unclear. Here, using the lung and diverse proteases, we identify a conserved injury signature of proteolytic stress marked by vascular disruption, red blood cell extravasation, and heme release that triggers oxidative stress. We show that alveolar macrophages act as primary sensors of this stress response, activating NRF2-dependent heme detoxification program and fibroblasts produce protease inhibitors to limit damage. Repeated exposure to proteolytic stress induces tissue adaptation and protects against subsequent injury and infection. These findings define a unifying framework for tissue-level proteolytic stress sensing and adaptation.

immunology↗

bioRxiv2025

Precocial ancestry of placental mammals

1Mammals exhibit two distinct reproductive strategies: altriciality, where neonates are highly underdeveloped, and precociality, where neonates are well-developed. The neonatal developmental state of deep nodes in mammalian phylogeny remains unresolved. Here, we use phylogenetic comparative methods to reconstruct the evolutionary history of neonatal maturity in mammals and demonstrate that the eutherian ancestor likely gave birth to precocial neonates. This finding contradicts the prevailing view that precociality evolved multiple times within the eutherian lineage. We contextualize this result with three lines of evidence. First, recent fossil evidence suggests that precocial life history traits arose early in therian evolution. Second, altricial eutherian neonates are markedly more developed at birth compared to altricial non-eutherians, suggesting a precocial ancestry in eutherian evolution. Third, reproductive traits that enable prolonged pregnancy originated in the stem lineage prior to the eutherian ancestor. Based on these findings, we propose an alternative model for the evolutionary history of precociality in mammals.

evolutionary biology↗

bioRxiv2018

Evolution of embryo implantation was enabled by the origin of decidual cells in eutherian mammals

Embryo implantation is the first step in the establishment of pregnancy in eutherian (Placental) mammals. Although viviparity evolved prior to the common ancestor of marsupials and eutherian mammals (therian ancestor), implantation is unique to eutherians. The ancestral therian pregnancy likely involved a short phase of attachment between the fetal and maternal tissues followed by parturition rather than implantation, similar to the mode of pregnancy found in marsupials such as the opossum. Embryo implantation in eutherian mammals as well as embryo attachment in opossum, induce a homologous inflammatory response in the uterus. Here, we elucidate the evolutionary mechanism by which the ancestral inflammatory fetal-maternal attachment was transformed into the process of implantation. We performed a comparative transcriptomic and immunohistochemical study of the gravid and non-gravid uteri of two eutherian mammals, armadillo (Dasypus novemcinctus) and hyrax (Procavia capensis); a marsupial outgroup, opossum (Monodelphis domestica); and compared it to previously published data on rabbit (Oryctolagus cuniculus). This taxon sampling allows inference of the eutherian ancestral state. Our results show that in the eutherian lineage, the ancestral inflammatory response was domesticated by suppressing a detrimental component viz. signaling by the cytokine IL17A, while retaining components that are beneficial to placentation, viz. angiogenesis, vascular permeability, remodeling of extracellular matrix. IL17A mediates recruitment of neutrophils to inflamed mucosal tissues, which, if unchecked, can damage the uterus as well as the embryo and lead to expulsion of the fetus. We hypothesized that the uterine decidual stromal cells, which evolved coincidentally with embryo implantation, evolved, in part, to prevent IL17A-mediated neutrophil infiltration. We tested a prediction of this hypothesis in vitro, and showed that decidual stromal cells can suppress differentiation of human naive T cells into IL17A-producing Th17 cells. Together, these results provide a mechanistic understanding of early stages of the evolution of the eutherian mode of pregnancy, and also identify a potentially ancestral function of an evolutionary novelty, the decidual stromal cell-type.

evolutionary biology↗

bioRxiv2018

The mammalian decidual cell evolved from a cellular stress response

Among animal species, cell types vary greatly in terms of number and kind. The broad range of number of cell types among species suggests that cell type origination is a significant source of evolutionary novelty. The molecular mechanisms giving rise to novel cell types, however, are poorly understood. Here we show that a novel cell type of eutherian mammals, the decidual stromal cell (DSC), evolved by rewiring an ancestral cellular stress response. We isolated the precursor cell type of DSCs, endometrial stromal fibroblasts (ESFs), from the opossum Monodelphis domestica. We show that, in opossum ESF, the majority of decidual core regulatory genes respond to decidualizing signals, but do not regulate decidual effector genes. Rather, in opossum ESF, decidual transcription factors function in apoptotic and oxidative stress response. We propose that the rewiring of cellular stress responses could be a general mechanism for the evolution of novel cell types.

evolutionary biology↗