Why do humans need thrombospondin-1?

Abstract

Matricellular proteins comprise several families of secreted proteins that function in higher animals at the interface between cells and their surrounding extracellular matrix. Targeted gene disruptions that result in loss of viability in mice have revealed critical roles for several matricellular proteins in murine embryonic development, including two members of the cellular communication network (CCN) gene family. In contrast, mice lacking single or multiple members of the thrombospondin (THBS) gene family remain viable and fertile. The frequency of loss of function mutants, identified using human deep exome sequencing data, provided evidence that some of the essential genes in mice, including Ccn1, are also essential genes in humans. However, a deficit in loss of function mutants in humans indicated that THBS1 is also highly loss-intolerant. In addition to roles in embryonic development or adult reproduction, genes may be loss-intolerant in humans because their function is needed to survive environmental stresses that are encountered between birth and reproduction. Laboratory mice live in a protected environment that lacks the exposures to pathogens and injury that humans routinely face. However, subjecting Thbs1−/− mice to defined stresses has provided valuable insights into functions of thrombospondin-1 that could account for the loss-intolerance of THBS1 in humans. Graphical Abstract

CGRP sensory neurons promote tissue healing via neutrophils and macrophages

“…Efferocytosis of neutrophils by macrophages was also greatly enhanced following macrophage treatment with TSP-1 (Fig. 3e), in line with a previous study suggesting that TSP-1 acts as a bridge between neutrophils and macrophages to facilitate efferocytosis 41 . Finally, TSP-1 enhanced expression of CD206 and arginase-1 in the presence of anti-inflammatory cytokines (IL-4/ IL-13 or IL-10), demonstrating that TSP-1 accelerates macrophage polarization towards an anti-inflammatory and pro-repair phenotype (Fig.…”

“…we tested whether TSP-1 affects neutrophil and macrophage migration and death, as well as efferocytosis and macrophage polarization. Although some reports have suggested that TSP-1 promotes neutrophil and macrophage migration 41 , we clearly observed an inhibition of migration when cells were treated with TSP-1, similarly to our observations with CGRP (Fig. 3c).…”

“…Notably, it has been reported that macrophages are the primary source of TSP-1 in wounds, and the absence of TSP-1 leads to impaired wound healing and prolonged inflammation 39,40 . Furthermore, increasing evidence suggests that TSP-1 is an important regulator in immune responses 41 . Thus, similar to the assays performed with CGRP, ) P < 0.001 P < 0.001 P < 0.001 P < 0.001 P < 0.001…”

A low thrombospondin‐1 serum concentration is related to increased bacteremia risk in lymphoma patients treated with BeEAM/BEAM conditioning regimen and autologous stem cell transplantation

“…15 Considering previous reports on the interaction of THBS1 with the immune system, the multifunctionality of this protein and miRNAs deregulation, we hypothesized that its concentrations might influence the incidence of severe infections during AHSCT, making THBS1 a potential biomarker of complications during ASCT. 16 This study aimed to assess the clinical value of a blood serum THBS-1 concentration that could serve as a predictive biomarker for infectious-related adverse events during AHSCT.…”

Exosomes Derived from Human Palatal Mesenchymal Cells Mediate Intercellular Communication During Palatal Fusion by Promoting Oral Epithelial Cell Migration

“…The top 10 proteins which were significantly up-regulated in HEPM-EXO showed a high intercorrelation and were reported to be associated with cell growth, cell communication and signal transduction. [25][26][27][28][29][30][31][32][33][34] HEPM-EXO may rely on some of these proteins to regulate the proliferation and migration of HIOEC. Among these proteins, THBS1 was frequently associated with exosomal regulation of cell migration.…”