‘Youthful’ phenotype of c-Kit+ cardiac fibroblasts

• Published in: Cellular and molecular life sciences : CMLS Vol. 79; no. 8; p. 424
• Main Authors: Firouzi, Fareheh, Echeagaray, Oscar, Esquer, Carolina, Gude, Natalie A., Sussman, Mark A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-08-2022; Springer Nature B.V
• Subjects: Aging; Animals; Biochemistry; Biological properties; Biology; Biomedical and Life Sciences; Biomedicine; c-Kit protein; Caspase-3; Cell Biology; Cell migration; Cell proliferation; Cell survival; Extracellular signal-regulated kinase; Fibroblasts; Fibroblasts - metabolism; Flow cytometry; Fluorescence; Genotype & phenotype; Green fluorescent protein; Heart; Heterogeneity; Immunohistochemistry; Injuries; Interstitial cells; Kinases; Life Sciences; Markers; Mice; Original Article; Phenotype; Phenotypes; Physical characteristics; Protein-tyrosine kinase receptors; Proto-Oncogene Proteins c-kit - genetics; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Signaling; Transcriptomes; Tyrosine; c-Kit; Youthful; Fibroblast; Cardiac; DDR2
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-022-04449-1

Cardiac fibroblast (CF) population heterogeneity and plasticity present a challenge for categorization of biological and functional properties. Distinct molecular markers and associated signaling pathways provide valuable insight for CF biology and interventional strategies to influence injury response and aging-associated remodeling. Receptor tyrosine kinase c-Kit mediates cell survival, proliferation, migration, and is activated by pathological injury. However, the biological significance of c-Kit within CF population has not been addressed. An inducible reporter mouse detects c-Kit promoter activation with Enhanced Green Fluorescent Protein (EGFP) expression in cardiac cells. Coincidence of EGFP and c-Kit with the DDR2 fibroblast marker was confirmed using flow cytometry and immunohistochemistry. Subsequently, CFs expressing DDR2 with or without c-Kit was isolated and characterized. A subset of DDR2
+
CFs also express c-Kit with coincidence in ~ 8% of total cardiac interstitial cells (CICs). Aging is associated with decreased number of c-Kit expressing DDR2
+
CFs, whereas pathological injury induces c-Kit and DDR2 as well as the frequency of coincident expression in CICs. scRNA-Seq profiling reveals the transcriptome of c-Kit expressing CFs as cells with transitional phenotype. Cultured cardiac DDR2
+
fibroblasts that are c-Kit
+
exhibit morphological and functional characteristics consistent with youthful phenotypes compared to c-Kit
−
cells. Mechanistically, c-Kit expression correlates with signaling implicated in proliferation and cell migration, including phospho-ERK and pro-caspase 3. The phenotype of c-kit
+
on DDR2
+
CFs correlates with multiple characteristics of ‘youthful’ cells. To our knowledge, this represents the first evaluation of c-Kit biology within DDR2
+
CF population and provides a fundamental basis for future studies to influence myocardial biology, response to pathological injury and physiological aging.