Increased CD47 and MHC Class I Inhibitory Signals Expression in Senescent CD1 Primary Mouse Lung Fibroblasts

Abstract

Cellular senescence is more than a proliferative arrest in response to various stimuli. Senescent cells (SC) participate in several physiological processes, and their adequate removal is essential to maintain tissue and organism homeostasis. However, SC accumulation in aging and age-related diseases alters the tissue microenvironment leading to deterioration. The immune system clears the SC, but the specific scenarios and mechanisms related to recognizing and eliminating them are unknown. Hence, we aimed to evaluate the existence of three regulatory signals of phagocytic function, CD47, major histocompatibility complex class I (MHC-I), and calreticulin, present in the membrane of SC. Therefore, primary fibroblasts were isolated from CD1 female mice lungs, and stress-induced premature senescence (SIPS) was induced with hydrogen peroxide. Replicative senescence (RS) was used as a second senescent model. Our results revealed a considerable increment of CD47 and MHC-I in RS and SIPS fibroblasts. At the same time, no significant changes were found in calreticulin, suggesting that those signals might be associated with evading immune system recognition and thus averting senescent cells clearance.

Cancer-Associated Fibroblast Mimetic AIE Probe for Precision Imaging-Guided Full-Cycle Management of Ovarian Cancer Surgery

“…Compared with HMSN-probe, CAF-probe has a longer circulation time in vivo (Figure B), and therefore, has better drug utilization and enhanced permeability and retention (EPR) effect. – Effective avoidance of probe clearance by the reticuloendothelial system is a challenge that must be addressed for its in vivo application. Activation of the CD47-SIRPα signaling pathway can have the ability to avoid phagocytosis of targets by macrophages, while CAFs naturally express CD47 and inherit it to CAF-probe. , HMSN-probe and CAF-probe were injected into mice separately, and the probes in the spleen were detected by CLSM. As shown in Figure C, the accumulation of CAF-probe in the spleen is less than that of HMSN-probe, indicating that CAF-probe is cleared less by the reticuloendothelial system and indirectly indicating the high bioavailability of CAF-probe.…”

“…Activation of the CD47-SIRPα signaling pathway can have the ability to avoid phagocytosis of targets by macrophages, while CAFs naturally express CD47 and inherit it to CAF-probe. 46,47 HMSN-probe and CAF-probe were injected into mice separately, and the probes in the spleen were detected by CLSM. As shown in Figure 3C, the accumulation of CAF-probe in the spleen is less than that of HMSN-probe, indicating that CAF-probe is cleared less by the reticuloendothelial system and indirectly indicating the high bioavailability of CAF-probe.…”

Single-cell and spatial detection of senescent cells using DeepScence

“…T cells and epithelial cells are among the top interaction targets of SnCs 12,29 (Figure 2k), consistent across human and mouse (correlation=0.417, Figure 2l, Supplementary Table S4). Several key pathways known as hallmarks of cellular senescence are consistently enriched across tissues (Figure 2m), including COLLAGEN, which is responsible for extracellular matrix remodeling and enlarged phenotypes of senescent cells 30-32 ; LAMININ, corresponding to the loss of laminin B1 that compromises nuclear integrity in senescent cells 1,33 ; MHC-I, which is elevated in senescent cells 34,35 ; and MIF, which is involved in senescence-associated inflammation and oxidative stress response pathways 36,37 . These pathways are again consistent across human and mouse (correlation=0.816, Figure 2n, Supplementary Table S5).…”

Cellular aging and immunity

“…Defective expression of the "eat me" signal calreticulin, a ligand required to activate engulfment receptors on phagocytic cells, results in cellular resistance to efferocytosis, and apoptotic cells fail to be cleared by neighboring macrophages. A proportion of aged and cancerous cells are susceptible to being "labeled" by macrophage-secreted calreticulin and are cleared from tissue (Feng et al, 2018;Hernández-Mercado et al, 2021).…”