Lymphatic vessels use Reelin protein to help regulate embryonic heart growth

A Northwestern Medicine study has uncovered a previously unknown signaling system that helps regulate heart growth during development, according to the study published in the journal Genes & Development.

The study reveals that lymphatic vessels do far more than just transport fluid and immune cells, according to Guillermo Oliver, Ph.D., the Thomas D. Spies Professor of Lymphatic Metabolism and senior author of the study.

In the study, Oliver and his collaborators used single-cell RNA sequencing and genetically engineered mouse models to identify a signaling pathway linking cardiac lymphatics, the heart’s outer lining (epicardium), and key growth genes that together help regulate cardiac growth.

The work builds on earlier discoveries from the Oliver laboratory showing that lymphatic vessels secrete a protein called Reelin that promotes heart growth by promoting cardiomyocyte proliferation. The current study shows that Reelin’s influence extends beyond heart muscle cells, helping maintain the epicardium, a thin layer of tissue surrounding the heart that is essential for normal cardiac development.

Protein’s reach extends outward

The team found that hearts lacking lymphatic-derived Reelin developed significant defects in the epicardium and lost specific populations of fibroblasts—cells that help build and support the heart’s structure. The investigators also observed reduced numbers of epicardial cells expressing two critical cardiac factors: the transcription factor WT1 and the growth factor insulin-like growth factor-1 (IGF-1).

“We recently identified the cardiac lymphatic vasculature as an unexpected regulator of heart size during embryonic development,” Oliver said. “Here, by combining single-cell RNA sequencing with loss-of-function mouse models, we uncover another novel and unexpected critical regulatory network also participating in this process.”

The findings may help answer one of developmental biology’s most fundamental questions: how organs achieve their correct size.

“When you don’t have Reelin, the epicardium is defective,” Oliver said. “We know that normally Reelin controls cardiomyocyte proliferation, but now we also know that it is essential for the maintenance and expansion of other cardiac cell types, including the epicardium and fibroblasts, and the expression of WT1 and IGF-1, which are responsible for the growth of the heart.”

Clues from human mini-hearts

To explore how Reelin acts on human tissue, the investigators turned to laboratory-grown human “epicardioids,” three-dimensional organoids that mimic features of the developing heart. Treating these mini-hearts with Reelin protein increased the expression of multiple epicardial markers, indicating that it promoted epicardial cell fate and supporting the idea that Reelin directly influences epicardial maintenance during development and induces epicardial fate in the adult heart.

The findings suggest that lymphatics’ beneficial effect during adult cardiac injury may be partially mediated by Reelin reactivating the dormant epicardium, leading to more efficient repair, Oliver said.

“Reelin expression in cardiac lymphatics declines progressively after birth and becomes nearly undetectable by day seven,” Oliver said. “This postnatal decrease coincides with the cessation of cardiac regeneration in newborn mice, suggesting that loss of Reelin may contribute to the arrest of these processes.”

Lymphatics as growth sentinels

Oliver and his research group now suspect lymphatic vessels may function as organ-wide monitoring systems that help determine when growth is complete.

“What we propose is that it’s possible that lymphatics function as organ-level quality control systems,” Oliver said. “The lymphatics, as they grow into a developing organ and monitor functional features such as interstitial fluid pressure, waste accumulation and tissue stiffness, are saying, “Okay, everything is looking good; keep growing, keep proliferating. Then, at some point that’s good enough, stop there.'”

Beyond advancing understanding of heart development, the findings could inform future approaches for repairing damaged hearts and investigating congenital heart defects, Oliver said.

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Lisa Lock

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