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Thrombospondin-1, CD47, and SIRPa display cell-speciﬁc molecular signaturesin human islets and pancreata

ABSTRACT: Thrombospondin-1 (TSP1) is a secreted protein minimally expressed in health but increased in disease and age. TSP1 binds tothe cell membrane receptor CD47, which itself engages signal regulatory protein a (SIRPa), and the latter creates a checkpointfor immune activation. Individuals with cancer administered checkpoint-blocking molecules developed insulin-dependent diabe-tes. Relevant to this, CD47 blocking antibodies and SIRPa fusion proteins are in clinical trials. We characterized the molecularsignature of TSP1, CD47, and SIRPa in human islets and pancreata. Fresh islets and pancreatic tissue from nondiabetic individu-als were obtained. The expression of THBS1, CD47, and SIRPA was determined using single-cell mRNA sequencing, immunoﬂuo-rescence microscopy, Western blot, and ﬂow cytometry. Islets were exposed to diabetes-afﬁliated inﬂammatory cytokines andchanges in protein expression were determined. CD47 mRNA was expressed in all islet cell types. THBS1 mRNA was restrictedprimarily to endothelial and mesenchymal cells, whereas SIRPA mRNA was found mostly in macrophages. Immunoﬂuorescencestaining showed CD47 protein expressed by b cells and present in the exocrine pancreas. TSP1 and SIRPa proteins were notseen in islets or the exocrine pancreas. Western blot and ﬂow cytometry conﬁrmed immunoﬂuorescent expression patterns.Importantly, human islets produced substantial quantities of secreted TSP1. Human pancreatic exocrine and endocrine tissueexpressed CD47, whereas fresh islets displayed cell surface CD47 and secreted TSP1 at baseline and in inﬂammation. Theseﬁndings suggest unexpected effects on islets from agents that intersect TSP1-CD47-SIRPa

ORGANISM(S): Homo sapiens

PROVIDER: GSE328522 | GEO | 2026/04/20

REPOSITORIES: GEO

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Project description:CD47 is a transmembrane glycoprotein that is ubiquitously expressed in different organs and tissues (Barclay and Van den Berg 2014; Liu, et al. 2017). In the human immune system, CD47 interacts with some integrins, two counter-receptor signal regulator protein (SIRP) family members, and the secreted thrombospondin-1 (TSP1) (Barclay and Van den Berg 2014; Gao, et al. 2016; Kaur, et al. 2013; Oldenborg, et al. 2000). CD47 has two established roles in the immune system. The CD47-SIRPα interaction was identified as a critical innate immune checkpoint, which delivers an antiphagocytic signal to macrophages and inhibits neutrophil cytotoxicity (Martínez- Sanz, et al. 2021). Its interaction with inhibitory SIRPα is a physiological anti-phagocytic “don’t eat me” signal on circulating red blood cells that is co-opted by cancer cells (Matlung, et al. 2017). Many malignant cells overexpress CD47 (Betancur, et al. 2017; Chao, et al. 2011; Jaiswal, et al. 2009; Majeti, et al. 2009; Oronsky, et al. 2020; Petrova, et al. 2017). CD47/SIRPα-targeted therapeutics have been developed to overcome this immune checkpoint for cancer treatment (Kaur, et al. 2020; Matlung, et al. 2017). Secondly, engagement of CD47 on T cells by TSP1 regulates their differentiation and survival (Grimbert, et al. 2006; Lamy, et al. 2007) and inhibits T cell receptor signaling and antigen presentation by dendritic cells (DCs) (Kaur, et al. 2014; Li, et al. 2002; Liu, et al. 2015; Miller, et al. 2013; Soto-Pantoja, et al. 2014; Weng, et al. 2014). TSP1/CD47 signaling has similar inhibitory functions to limit NK cell activation (Kim, et al. 2008; Nath, et al. 2018; Nath, et al. 2019; Schwartz, et al. 2019) and IL1β production by macrophages (Stein, et al. 2016). CD47 is therefore a checkpoint that regulates both innate and adaptive immunity. The recent understanding of CD47 antagonism associated with increased antigen presentation by DCs (Liu, et al. 2016) and natural killer cell cytotoxicity (Nath, et al. 2019) contributes to the heightened interest in CD47 as a therapeutic target (Kaur, et al. 2020).

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Thrombospondin-1, CD47, and SIRPa display cell-speciﬁc molecular signaturesin human islets and pancreata

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