Research

Heart disease is the leading cause of death worldwide, posing an immense burden on global health. A significant roadblock to effective cardiac disease treatment lies in the limited capacity of the adult heart to regenerate. In contrast, the newborn mouse heart can effectively regrow the damaged tissue. Our lab aims to use systems-level approaches to discover the basic biological mechanisms underlying neonatal heart regeneration. We are interested in studying how cells in the neonatal heart detect injury signals and initiate dedifferentiation, proliferation, and eventually redifferentiation to form functional new cells? How do different cell types within the heart interact and guide each other in reconstructing the damaged tissue with appropriate cellular composition and tissue architecture? How is genetic information regulated in space and time to instruct a three-dimensional organization of cells within the regenerated heart tissue? We leverage the information learned by answering those questions to identify therapeutic targets and translate our findings into studies of human cells and therapies for heart disease patients. The long-term goal of our research program is to understand the mechanisms underlying the distinct reparative abilities of different cardiac cell types during neonatal heart regeneration vs. pathological remodeling in adults, and ultimately to generate a comprehensive cellular and molecular blueprint for targeting cardiac regeneration in patients.

Cardiomyocytes (CM) are the heart muscle cells integral for generating contractile force. Restoration of lost CMs after injury plays a vital role in driving the heart's functional recovery. While it is known that newly formed CMs during neonatal heart regeneration are derived from preexisting CMs, our understanding remains limited regarding the source of these generative CMs, their specific location within the heart, and their interactive behaviors during regeneration. We have identified a novel CM population that is unique to newborn mice and exhibits regeneration features following injury (Cui, et al., Dev Cell, 2020). We're currently employing several innovative genetic mouse models coupled with cutting-edge single-cell genomic approaches to identify and trace these regenerative CMs during heart regeneration and uncover their gene regulatory mechanisms that govern their regenerative responses. Specifically, we (1) develop novel genetic mouse models to label regenerating CMs, (2) investigate the molecular consequences of each cell division during regeneration, and (3) study spatial patterning and cellular environment of regenerating CMs.

The origin and identity of regenerative cardiomyocytes.

Plasticity of cardiac stromal cells in regeneration and disease.

Stromal cells, once believed to only provide structural support, are now acknowledged as key regulators in various tissues, including the heart. Cardiac stromal cells play a crucial role in maintaining tissue homeostasis through their control of extracellular matrix remodeling, paracrine signaling, and communication with the immune system. They also play a significant role in heart regeneration, as well as the development and progression of various heart diseases. Despite this, our understanding of the dynamic facets of the cardiac stroma and the mechanisms underlying their ability to differentially regulate cardiac regeneration and disease is still limited. Our single-cell transcriptomic studies have provided insight into the phenotypic plasticity of cardiac stromal cells in response to injury, revealing distinct transcriptional profiles in regeneration and disease remodeling (Wang, Cui, et al. Cell Reports, 2021). We are studying the regulatory mechanisms underlying their plasticity, with the goal to identify novel molecular targets to guide these cells in supporting heart repair and regeneration in adults. With this regard, our research focuses on (1) how cardiac resident fibroblasts differentially respond to injury during disease and regeneration, (2) what is the lineage contribution and transcriptional regulation of epicardial cell differentiation, and (3) Gene Regulatory Networks that govern the phenotype of cardiac cells in development and disease

Role of adaptive stress response in tissue regeneration and repair

The specific mechanisms by which cells in regenerative tissues adapt to stress conditions caused by injury during the regeneration process are still not fully understood. In our previous work (Cui, et al. Nat. Commun, 2021), we demonstrated that regenerative cardiomyocytes (CMs) not only undergo cell-cycle activation but also upregulate cell survival pathways. This finding suggests a potential co-regulation between cardioprotection and heart regeneration. Traditionally, cardioprotection and heart regeneration were believed to involve distinct mechanisms. However, protecting cardiomyocytes from injury or disease stimuli is an essential prerequisite for any meaningful regenerative response. Our research focuses on exploring the unique stress adaptive mechanisms of neonatal regenerative CMs and investigating how these mechanisms can be harnessed to enhance the reparative potential of adult hearts. We aim to demonstrate the therapeutic potential of these approaches using AAV (adeno-associated virus) and modified RNA molecules.

High-throughput functional screens for regeneration essential factors

We employ methods of network analyses incorporating single cell-transcriptome and chromatin accessibility as well as cutting-edge machine learning approaches to identify essential regulatory nodes for heart regeneration. We further study the pro-regenerative effects of these network elements through AAV-based in vivo loss- and gain-of-function screening approaches. The results will provide a high-resolution molecular framework of regenerative responses in CMs and uncover many gene targets that can inform development of new strategies for promoting regeneration in human hearts.