PhD Position in Angiocrine control of cardiomyocyte dedifferentiation, cell cycle entry, and cytokinesis

Summary

Cardiovascular disease and subsequent heart failure account for a large proportion of morbidity and mortality worldwide, and there remains a pressing need to promote heart regeneration following myocardial injury. As part of the Collaborate Research Center 1366 (https://www.sfb1366.de/), this project aims at (1) elucidating how endothelial cells regulate cardiomyocyte behavior following injury and (2) identifying novel regulators to promote heart regeneration in adult mammals.

Zebrafish and neonatal mice efficiently regenerate their heart after injury via cardiomyocyte (CM) dedifferentiation and proliferation (Schnabel*, Wu* et al., 2011; Wu et al., 2016; Bertozzi*, Wu* et al., 2021). In contrast, adult mammalian heart regeneration is hampered by inefficient CM renewal due to (a) low cell cycle re-entry and (b) polyploidization (i.e., lack of cytokinesis to generate new cells) (Wu et al., 2020; Beisaw and Wu, 2022). A mechanistic understanding of how these two processes is regulated will help devise therapeutic strategies to promote CM renewal and heart regeneration in adult mammals.

Endothelial cells play crucial roles during heart development, homeostasis, and regeneration via paracrine signaling (Marin-Juez, et al., 2019; El-Sammak et al., 2022). However, the molecular mechanisms by which endothelial cells regulate CM dedifferentiation, cell cycle entry, and cytokinesis remains poorly understood. To address this question, we will

(1) Identify paracrine factors from regenerating endothelium that promote CM dedifferentiation and subsequent cell cycle re-entry (in collaboration with Prof. Didier Stainier from MPI for Heart and Lung Research)
(2) Investigate whether and how cardiac endothelial cells promote CM polyploidization during postnatal mouse heart development
(3) Test candidate dedifferentiation and cytokinesis inducers in promoting adult heart regeneration following myocardial infarction

Altogether, this project will (a) provide novel insights into the molecular mechanisms of cardiac regeneration and (b) identify potential therapeutic targets to promote heart regeneration in adult mammals.

We are looking for a motivated PhD candidate to spearhead this project using a combination of in vitro (primary cultures), in vivo (regenerating and non-regenerating models), and OMIC approaches. Prior experiences with primary cultures, mouse genetics, and FELASA qualification are desirable. Successful candidate will work in the Ploidy and Organ Physiology Laboratory (European Center for Angioscience, Heidelberg University), led by Dr. Chi-Chung Wu, and benefit from our national and international connections/collaborations with research groups in both zebrafish and mammalian fields. Further information can be found on https://www.ccwulab.com/.

Reference

Modulation of Mammalian Cardiomyocyte Cytokinesis by the Extracellular Matrix (DOI: 10.1161/CIRCRESAHA.119.316303)

Spatially Resolved Genome-wide Transcriptional Profiling Identifies BMP Signaling as Essential Regulator of Zebrafish Cardiomyocyte Regeneration (DOI: 10.1016/j.devcel.2015.12.010)

Cardiomyocyte maturation and its reversal during cardiac regeneration (DOI: 10.1002/dvdy.557)

Methods that will be used

Primary cultures, OMICs, mouse and zebrafish models

Cooperation partners

Didier Stainier (MPI for Heart and Lung Research, Bad Nauheim), members of the CRC1366 – Vascular Control of Organ Function.

Personal qualifications

Strong interest in developmental and regeneration biology. Prior experiences with primary cultures, mouse genetics, and FELASA qualification are desirable but not necessary.

Keywords

cytokinesis, heart regeneration, cardiomyocyte, cell cycle, dedifferentiation