Fetal Hypoxia Impacts on Proliferation and Differentiation of Sca-1+ Cardiac Progenitor Cells and Maturation of Cardiomyocytes: A Role of MicroRNA-210

Abstract

Hypoxia is one of the most frequent and severe stresses to an organism’s homeostatic mechanisms, and hypoxia during gestation has profound adverse effects on the heart development increasing the occurrence of congenital heart defects (CHDs). Cardiac progenitor cells (CPCs) are responsible for early heart development and the later occurrence of heart disease. However, the mechanism of how hypoxic stress affects CPC fate decisions and contributes to CHDs remains a topic of debate. Here we examined the effect of hypoxic stress on the regulations of CPC fate decisions and the potential mechanism. We found that experimental induction of hypoxic responses compromised CPC function by regulating CPC proliferation and differentiation and restraining cardiomyocyte maturation. In addition, echocardiography indicated that fetal hypoxia reduced interventricular septum thickness at diastole and the ejection time, but increased the heart rate, in mouse young adult offspring with a gender-related difference. Further study revealed that hypoxia upregulated microRNA-210 expression in Sca-1+ CPCs and impeded the cell differentiation. Blockage of microRNA-210 with LNA-anti-microRNA-210 significantly promoted differentiation of Sca-1+ CPCs into cardiomyocytes. Thus, the present findings provide clear evidence that hypoxia alters CPC fate decisions and reveal a novel mechanism of microRNA-210 in the hypoxic effect, raising the possibility of microRNA-210 as a potential therapeutic target for heart disease.

High cardiomyocyte diversity in human early prenatal heart development

“…The second largest ventricular CM cluster (cluster 1) was associated with GO terms related to glycolysis 22 and response to hypoxia, 23 indicating high energy production. Moreover, this cluster strongly differentially expressed the gene HEY2 (p_val_adj 2.5 × 10 −27 ) ( Figures S2 A and S2B), which is a downstream effector of NOTCH signaling that plays a pivotal role in the maturation of compact CMs .…”

High cardiomyocyte diversity in human early prenatal heart development

“…The second largest ventricular CM cluster (cluster 1) was associated with GO terms related to glycolysis (Graham and Huang, 2021) and response to hypoxia (Meng et al, 2020), indicating high energy production. Moreover, this cluster strongly differentially expressed the gene HEY2 (p_val_adj 2.5 × 10 −27 ) (Figure S2A), which is a downstream effector of NOTCH signaling that plays a pivotal role in the maturation of compact CMs (Firulli et al, 2020).…”

Antenatal Hypoxia Accelerates the Onset of Alzheimer’s Disease Pathology in 5xFAD Mouse Model

“…Pregnant C57BL/6J mice were randomly divided into two groups to receive either normoxia or hypoxia treatment during gestation. To induce hypoxic responses, the animals were placed in their home cages in a hypoxia chamber with 11.5 or 10.5% O 2 generated by an Altitude Generator (Everest Summit II; Hypoxico Altitude Training System, New York, NY, USA) from days 14.5 to 17.5 of gestation (E14.5–E17.5), as described previously (Gortner et al, 2005 ; Tomlinson et al, 2010 ; Meng et al, 2020 ). At the end of exposure, the dams were returned to normoxic conditions.…”