The mesenchymal context in inflammation, immunity and cancer

Abstract

Mesenchymal cells are mesoderm-derived stromal cells that are best known for providing structural support to organs, synthesizing and remodeling the extracellular matrix (ECM) and regulating development, homeostasis and repair of tissues. Recent detailed mechanistic insights into the biology of fibroblastic mesenchymal cells have revealed they are also significantly involved in immune regulation, stem cell maintenance and blood vessel function. It is now becoming evident that these functions, when defective, drive the development of complex diseases, such as various immunopathologies, chronic inflammatory disease, tissue fibrosis and cancer. Here, we provide a concise overview of the contextual contribution of fibroblastic mesenchymal cells in physiology and disease and bring into focus emerging evidence for both their heterogeneity at the single-cell level and their tissue-specific, spatiotemporal functional diversity.

Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

“…Fibroblasts are present in all tissues and adopt specialized phenotypes and activation states to perform both essential functions in development, wound-healing, and maintenance of tissue architecture, as well as pathological functions such as tissue inflammation, fibrosis, and cancer responses (Koliaraki et al, 2020).…”

“…Fibroblasts are present in all tissues and adopt specialized phenotypes and activation states to perform both essential functions in development, wound-healing, and maintenance of tissue architecture, as well as pathological functions such as tissue inflammation, fibrosis, and cancer responses (Koliaraki et al, 2020). Recent studies of chronic inflammatory disease have leveraged advances in high-throughput single-cell genomics, particularly single-cell RNA-sequencing (scRNAseq) to identify molecularly distinct fibroblast populations associated with pathological inflammation in different anatomical sites (Adams et al, 2020; Habermann et al, 2020; Huang et al, 2019; Kinchen et al, 2018; Martin et al, 2019; Mizoguchi et al, 2018; Smillie et al, 2019; Zhang et al, 2019).…”

Cross-tissue single-cell transcriptomics reveals organizing principles of fibroblasts in health and disease

“…Fibroblasts populate all tissues of the body, delineate the topography of organs via the production and remodeling of extracellular matrix proteins (ECMs) 1 and support tissue-resident cell types including macrophages, T cells, B cells, innate-like lymphocytes, dendritic cells, hematopoietic stem cells and endothelial cells 2,3 . These mesenchymal cells appear to perform both general functions associated with their lineage regardless of context and specialized programs suited to the needs of the tissue to maintain organ homeostasis.…”

“…Technological advances, such as single-cell RNA-sequencing (scRNA-seq), have revealed an intriguing degree of intra-tissue fibroblast heterogeneity 2 , though whether these insights apply across tissues is unknown. Understanding fibroblast inter-tissue population structure has clinical relevance as subtypes of fibroblasts drive inflammation and tissue destruction in arthritis 7–10 , promote malignancy in cancer 11–15 and deposit ECMs that promotes tissue dysfunction in fibrotic indications such as idiopathic pulmonary fibrosis (IPF) 1 .…”

Perinatal Cells: A Promising COVID-19 Therapy?

“…Mesenchymal stromal cells (MSCs) represent a possible alternative treatment for COVID-19 aimed at counteracting the damage and organ failure due to inflammatory and fibrotic processes induced by SARS-CoV2, as well as responding to many of the symptoms induced by the viral infection. In fact, MSCs have been studied for years in regenerative medicine for the immunomodulatory properties that make them suitable for the treatment of many chronic or degenerative diseases, where the immune response is dysregulated (Shi et al, 2018;Koliaraki et al, 2020). Furthermore, these cells are also characterized by antimicrobial properties (Alcayaga-Miranda et al, 2017) and reduced expression of HLA-II strongly reducing the risk of allograft rejection (Ryan et al, 2005).…”