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Transfer learning of an in vivo-derived senescence signature identifies conserved tissue-specific senescence across species and diverse pathologies [bulk RNA-seq]

ABSTRACT: Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite their pathological role and therapeutic interest, senescent cells’ (SnCs) phenotype in vivo remains unclear. Here, we developed an in vivo-derived senescence signature using a foreign body response (FBR) fibrosis model in a SnC reporter mouse. We identified stromal cells as the primary SnC in the FBR and produced a SnC transcriptomic signature. Transfer learning identified SnCs in diverse murine and human data single cell RNAseq (scRNAseq) sets. Further, we found both conserved and tissue-specific SnC and secretory phenotypes. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34-CSF1R-TGFbR signaling axis, contributing to angiogenic and fibrotic responses. Overall, our study identifies a conserved transcriptional profile of SnCs and transfer learning approach that may be broadly applied to identify and understand senescence in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE199864 | GEO | 2023/12/07

REPOSITORIES: GEO

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Project description:In vitro cultures of primary cardiac fibroblasts (CFs), the major extracellular matrix (ECM)-producing cells of the heart, are used to determine molecular mechanisms of cardiac fibrosis. However, the supraphysiologic stiffness of tissue culture polystyrene (TCPS) automatically triggers the conversion of CFs into an activated myofibroblast-like state, and serial passage of the cells results in the induction of replicative senescence. These dramatic phenotypic switches confound interpretation of experimental data obtained with cultured CFs. In an attempt to circumvent TCPS-induced activation and senescence of CFs, we utilized poly (ethylene glycol) (PEG) hydrogels as cell culture platforms with low and high stiffness formulations to mimic healthy and fibrotic cardiac ECM, respectively. As hypothesized, low hydrogel stiffness converted activated CFs into a quiescent state with reduced abundance of a-smooth muscle actin (a-SMA)-containing stress fibers. Unexpectedly, lower substrate stiffness concomitantly augmented CF senescence, marked by elevated senescence-associated b-galactosidase (SA-b-Gal) activity and increased expression of p16 and p21, which are cyclin-dependent kinase (CDK) inhibitors and markers of senescence. Using dynamically stiffening hydrogels with phototunable crosslinking capabilities, we demonstrate that substrate-induced CF senescence is partially reversible. RNA-sequencing analysis revealed widespread transcriptional reprogramming of CFs cultured on low stiffness hydrogels, with a dramatic reduction in the expression of profibrotic genes encoding ECM proteins, and an attendant increase in expression of NF-kB-responsive inflammatory genes that typify the senescence-associated secretory phenotype (SASP). Our findings further demonstrate that alterations in matrix stiffness profoundly impact CF cell state transitions, and suggest mechanisms by which CFs change phenotype in vivo depending on the stiffness of the myocardial microenvironment to which they are exposed.

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Transfer learning of an in vivo-derived senescence signature identifies conserved tissue-specific senescence across species and diverse pathologies [bulk RNA-seq]

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