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Updated: Jun 13, 2026
Generation and Expansion of Human Cardiomyocytes from Patient Peripheral Blood Mononuclear Cells
Published on: February 12, 2021
Endogenous retinoic acid regulates cardiac progenitor differentiation
Song-Chang Lin1, Pascal Dollé, Lucile Ryckebüsch
1Departments of Medicine and Molecular and Cellular Biology, Center for Cardiovascular Development, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
Retinoic acid (RA) has several established functions during cardiac development, including actions in the fetal epicardium required for myocardial growth. An open question is if retinoid effects are limited to growth factor stimulation pathway(s) or if additional actions on uncommitted progenitor/stem populations might drive cardiac differentiation. Here we report the dual effects of RA deficiency on cardiac growth factor signaling and progenitor/stem biology using the mouse retinaldehyde dehydrogenase 2 (Raldh2) knockout model. Although early heart defects in Raldh2(-/-) embryos result from second-heart-field abnormalities, it is unclear whether this role is transient or whether RA has sustained effects on cardiac progenitors. To address this, we used transient maternal RA supplementation to overcome early Raldh2(-/-) lethality. By embryonic day 11.5-14.5, Raldh2(-/-) hearts exhibited reduced venticular compact layer outgrowth and altered coronary vessel development. Although reductions in Fgf2 and target pERK levels occurred, no alterations in Wnt/beta-catenin expression were observed. Cell proliferation is increased in compact zone myocardium, whereas cardiomyocyte differentiation is reduced, alterations that suggest progenitor defects. We report that the fetal heart contains a reservoir of stem/progenitor cells, which can be isolated by their ability to efflux a fluorescent dye and that retinoid signaling acts on this fetal cardiac side population (SP). Raldh2(-/-) hearts display increased SP cell numbers, with selective increases in expression of cardiac progenitor cell markers and reduced differentiation marker levels. Hence, although lack of RA signaling increases cardiac SP numbers, simultaneous reductions in Fgf signaling reduce cardiomyocyte differentiation, possibly accounting for long-term defects in myocardial growth.
Insights
Retinoic acid (RA) deficiency impairs fetal heart development by affecting cardiac progenitor cells and growth factor signaling. Lack of RA increases stem cell populations but reduces cardiomyocyte differentiation, impacting myocardial growth.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Stem Cell Biology
Background:
- Retinoic acid (RA) is crucial for cardiac development, influencing myocardial growth via the fetal epicardium.
- The precise role of RA in cardiac progenitor/stem cell differentiation remains an open question.
- Retinaldehyde dehydrogenase 2 (Raldh2) knockout mice provide a model to study RA deficiency in cardiac development.
Purpose of the Study:
- To investigate the dual effects of RA deficiency on cardiac growth factor signaling and progenitor/stem cell biology.
- To determine if RA has sustained effects on cardiac progenitors beyond early heart field development.
- To elucidate the impact of RA signaling on fetal cardiac stem/progenitor populations.
Main Methods:
- Utilized the mouse retinaldehyde dehydrogenase 2 (Raldh2) knockout model.
- Employed transient maternal RA supplementation to manage early embryonic lethality.
- Analyzed cardiac morphology, gene expression (Fgf2, pERK, Wnt/beta-catenin), cell proliferation, and cardiomyocyte differentiation markers.
- Isolated and characterized fetal cardiac side population (SP) cells based on their dye efflux properties.
Main Results:
- Raldh2(-/-) embryos exhibited reduced ventricular compact layer outgrowth and altered coronary vessel development.
- RA deficiency led to increased cell proliferation but reduced cardiomyocyte differentiation in the compact zone myocardium.
- Raldh2(-/-) hearts showed increased numbers of cardiac SP cells with elevated progenitor cell markers and reduced differentiation markers.
- Reductions in Fgf2 and pERK levels were observed, while Wnt/beta-catenin expression remained unchanged.
Conclusions:
- RA signaling is essential for sustained cardiac progenitor/stem cell function and differentiation.
- RA deficiency increases the number of cardiac stem/progenitor cells but impairs their differentiation capacity.
- The interplay between RA signaling, FGF signaling, and cardiac progenitor cell dynamics contributes to long-term myocardial growth defects.
