Consequences of PDGFRα+ fibroblast reduction in adult murine hearts

Abstract

Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury. Fibroblast-ablated mice demonstrated a substantive reduction in cardiac fibroblasts, but fibrillar collagen and the ECM proteome were not overtly altered when evaluated by quantitative mass spectrometry and N-terminomics. However, the distribution and quantity of collagen VI, a microfibrillar collagen that forms an open network with the basement membrane, was reduced. In fibroblast-ablated mice, cardiac function was better preserved following angiotensin II/phenylephrine (AngII/PE)-induced fibrosis and myocardial infarction (MI). Analysis of cardiomyocyte function demonstrated altered sarcomere shortening and slowed calcium decline in both uninjured and AngII/PE infused fibroblast-ablated mice. After MI, the residual resident fibroblasts responded to injury, albeit with reduced proliferation and numbers immediately after injury. These results indicate that the adult mouse heart tolerates a significant degree of fibroblast loss with potentially beneficial impact on cardiac function after injury. The cardioprotective effect of controlled fibroblast reduction may have therapeutic value in heart disease.

Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis

“…PDGFRα is essential for cardiac fibroblast survival, 53 and reduction of PDGFRα+ fibroblasts in murine hearts resulted in improvement in cardiac function after injury. 54 We demonstrated that CDCP1 knockdown reduced HCF proliferation stimulated by PDGF-BB (Figure 4), suggesting a possible role for targeting CDCP1 to modulate cardiac fibrosis and function. An important and relevant finding was that CDCP1 knockdown significantly reduced sST2 expression (Figure 6).…”

Correcting dilated cardiomyopathy with fibroblast-targeted p38 deficiency

“…By contrast cardiac fibroblasts proliferated in response to the I61Q-dependent loss of myocyte tension generation ( Fig. 2f-k ), which is likely a permanent modification given cardiac fibroblasts are resistant to cell death and lack regulatory mechanisms for restricting cell number ( 49 – 51 ). Hence, the tissue alignment, compaction, and stiffness that resulted from fibroblast proliferation ( Fig.…”

Cardiomyocyte-fibroblast crosstalk in the postnatal heart

“…Similarly, ablation of platelet-derived growth factor receptor alpha (Pdgfrα)Cre expressing fibroblasts also results in decreased tissue stiffness and increased cardiomyocyte mitotic index postnatally ( Kuwabara et al, 2022a ). In adults, ablation of PdgfrαCre or PostnCre-expressing cardiac fibroblasts prevents severe scarring after myocardial injury ( Kanisicak et al, 2016 ; Kuwabara et al, 2022b ). Thus, cardiac fibroblasts, generated during development, differentiate into dynamic states in response to context dependent stimuli with differential responses related to ECM production and crosstalk with cardiomyocytes ( Figure 1 ).…”