Vitamin D Stimulates Cardiomyocyte Proliferation and Controls Organ Size and Regeneration in Zebrafish

Area of Science:

• Developmental Biology
• Regenerative Medicine
• Endocrinology

Background:

• Organ size regulation is crucial for development and regeneration, relying on mitogenic factors.
• Vitamin D is typically viewed as anti-proliferative, with limited understanding of its role in cell growth.
• Zebrafish models offer a powerful system for studying developmental and regenerative processes.

Purpose of the Study:

• To identify novel cardiomyocyte mitogens using a large-scale chemical screen in embryonic zebrafish.
• To investigate the role of vitamin D signaling in cell proliferation and organ size control.
• To explore vitamin D's impact on cardiac regeneration.

Main Methods:

• Large-scale chemical screening in embryonic zebrafish.
• Pharmacologic and genetic manipulation of vitamin D signaling pathways.
• Assessment of cell proliferation in various cell types and organ growth rates.
• Analysis of gene expression, including ErbB2 signaling pathways.
• Evaluation of cardiac regeneration following injury.

Main Results:

• Vitamin D analogs, such as alfacalcidol, demonstrated potent mitogenic effects on embryonic and adult cardiomyocytes in vivo.
• Vitamin D signaling modulated proliferation in multiple adult cell types and influenced growth rates in zebrafish.
• Tissue-specific vitamin D receptor (VDR) activation led to organ-restricted effects, including cardiomegaly.
• Alfacalcidol enhanced zebrafish heart regeneration after injury, while VDR blockade inhibited it.
• Alfacalcidol upregulated cardiac ErbB2 signaling, which was crucial for its mitogenic effects.

Conclusions:

• Vitamin D acts as a mitogen for cardiomyocytes and other cell types in zebrafish.
• Vitamin D signaling is a key regulator of organ size and regeneration.
• The findings suggest a novel mechanism involving vitamin D and ErbB2 signaling in cell proliferation and repair.