Heart work: towards the rebuilding of the heart – PhD Defense Mara Bouwman

During a heart attack, lack of blood flow causes heart muscle cells to die. The human heart cannot replace these cells. Instead, the damaged tissue turns into a scar, reducing its ability to pump blood. Currently, there is no treatment for patients with heart failure that can restore the heart cells or function, but interestingly, zebrafish can regenerate their injured hearts.

The Bakkers group studies genes that facilitate this process of regeneration. Essentially, a gene is an instruction in the DNA, telling cells what to do when active. “If we know what genes are important for heart regeneration in zebrafish, we can maybe use them to initiate heart regeneration in the non-regenerating mammalian heart,” Mara explains. A previous PhD student in the Bakkers group identified two genes, Prrx1b and Hgma1a, that are active during zebrafish heart regeneration, but not in injured mouse hearts. The question driving Mara’s research was whether these genes are required for zebrafish heart regeneration.

A scar-free heart after injury?

During her research, Mara discovered that Prrx1b is active in the outer layer of the zebrafish heart. Upon removing Prrx1b in zebrafish, she observed excessive scar formation and impaired heart muscle cell growth. This uncovered that Prrx1b plays an important role in balancing regeneration and scar tissue formation. Interestingly, scar tissue in the zebrafish heart is temporary: it gradually disappears as new heart tissue is formed. The cells that make scar tissue are eventually switched off during regeneration, leading to a scar-free heart and restored pumping efficiency.

Formation of new heart muscle

The second gene, Hmga1a, turned out to stimulate growth of new heart muscle cells. It does this by making specific genes more accessible without altering the genetic code. This works as an on switch, activating the genes that stimulate heart muscle cell growth. Mara succeeded in introducing Hmga1 in injured mouse hearts by delivering the gene into mouse heart cells, and found promising results: improved heart function, reduced scarring and the growth of new heart muscle cells. This suggests that it may be possible to induce heart regeneration even in mammals. Towards the end of her PhD, Mara started to investigate Hmga1 in human heart muscle cells, which yielded positive preliminary results.

In sum, Mara’s research uncovers that both Prrx1b and Hmga1a are required for heart regeneration in zebrafish. In the long run, her work could contribute to gene therapies that stimulate the repair of damaged heart tissue by inducing heart regeneration.

Lovely colleagues, great collaborations

Mara enjoyed her PhD very much. “I already did my master’s internship in Jeroen Bakkers’ lab and stayed for my PhD,” she says. “It’s a great environment with lovely colleagues and great collaborations.” A personal highlight was publishing her work on Hmga1 in early 2025. Like many PhD students, she had more project ideas than time allowed: “It required prioritizing in the end.”

The good news is that she does not have to leave all those ideas behind entirely, as she will stay on as a postdoc in the Bakkers Group to further investigate Hmga1 in mammals. Mara advises anyone considering a PhD: “Do not underestimate yourself! You know more than you think, and you will learn a lot.”