Work

Rescue of mitochondrial dysfunction through alteration of extracellular matrix composition in barth syndrome cardiac fibroblasts

Year: 2024

Type: article

Abstract: Fibroblast-ECM (dys)regulation is associated with a plethora of diseases. The ECM acts as a reservoir of inflammatory factors and cytokines that mediate molecular mechanisms within cardiac cell populations. The role of ECM-mitochondria crosstalk in the development and progression of cardiac disorders remains uncertain. We evaluated the influence of ECM produced by stromal cells from patients with the mitochondrial cardiomyopathy (Barth syndrome, BTHS) and unaffected healthy controls on cardiac fibroblast (CF) metabolic function. To do this, cell-derived matrices CDMs were generated from BTHS and healthy human pluripotent stem cell-derived CFs (hPSC-CF) and used as cell culture substrates. BTHS CDMs negatively impacted the mitochondrial function of healthy hPSC-CFs while healthy CDMs improved mitochondrial function in BTHS hPSC-CFs. Mass spectrometry comparisons identified 5 matrisome proteins differentially expressed in BTHS compared to healthy CDM. Our results highlight a key role for the ECM in disease through its impact on mitochondrial function. • Patient-specific CDMs are a useful cell culture platform to capture variability among disease patients. • ECM made by disease stromal cells negatively affects mitochondrial function and morphology of healthy cardiac fibroblasts. • The ECM-mitochondrial crosstalk may contribute to perpetuating the pathological presentation of BTHS. • Our findings suggest that genetic disease severity could be modulated by targeting the ECM.

Source: Biomaterials

DOI: 10.1016/j.biomaterials.2024.122922