CUHK Unveils the World’s First CD4+ Treg Cell Heart Regeneration Mechanism Offering a New Target for Heart Repair Treatment

The Chinese University of Hong Kong (CUHK)’s Faculty of Medicine (CU Medicine) has announced the world’s first discovery that CD4+Treg cells (CD4+ FOXP3+ regulatory T cells) in the immune system can precisely regulate MRG15, a key to neonatal cardiac regeneration. The team also uncovered the mechanism through which these cells stimulate heart development and repair. This groundbreaking research offers a novel therapeutic target and strategy for cardiac regenerative medicine, potentially overcoming the challenge of the heart’s inability to self-repair after injury. The findings, which will benefit patients with myocardial infarction and heart failure in China and worldwide, have been published in Circulation, a leading international journal in cardiovascular medicine.

The findings, which will benefit patients with myocardial infarction and heart failure in China and worldwide, have been published in a leading international journal in cardiovascular medicine. Photo source: CU Medicine

CUHK identifies CD4+ Treg cells as essential for cardiomyocyte regeneration

The heart is one of the most vital organs in the human body. In adults, damaged cardiomyocytes, the main type of muscle cells in the heart, cannot regenerate. However, neonatal hearts, when injured, have a transient yet significant capability to repair and regenerate. This capacity diminishes with age, which is a key reason why cardiovascular diseases such as myocardial infarction, heart failure and stroke remain among the deadliest conditions worldwide. According to the World Health Organization, nearly 20 million people die from cardiovascular diseases per year. The Chinese Center for Disease Control and Prevention figures indicate that cardiovascular diseases account for nearly 50% of deaths in the Chinese Mainland. In Hong Kong, one in six deaths is related to cardiovascular disease or stroke. (Data from Health Bureau of the Government of the Hong Kong Special Administrative Region of the People’s Republic of China)

To explore the links between neonatal cardiac repair and potential treatments for cardiovascular disease, Professor Kathy Lui Oi-lan and her team at CU Medicine have spent years investigating CD4+ Treg cells, a T cell subset that modulates immune responses. While Treg cells are known to play a role in controlling autoimmune diseases by controlling excessive immune reactions according to the winning discoveries of Nobel Prize in Physiology or Medicine (2025), CU Medicine unveiled its non-immunoregulatory function, as published in leading journal Theranostics in 2019. The study showed that when neonatal hearts were injured, it activated CD4+ Treg cells which secreted factors via paracrine mechanisms to directly promote cardiomyocyte proliferation. This discovery provided important clues for developing innovative therapies for cardiac repair and regeneration. However, the specific underlying mechanisms remained unclear.

Unlocking MRG15 as the key to heart regeneration

After six years of research, the team has finally uncovered how CD4+ Treg cells regulate the transient regenerative capacity of the neonatal heart, and the findings were published in Circulation.Experimental findings confirmed that CD4+ Treg cells can control a chromatin-modifying protein known as MRG15. It is highly expressed in neonatal cardiomyocytes but its expression is significantly downregulated as the heart matures.

To further study the role of MRG15 in cardiac regeneration, the team employed a gene knockout mouse model to delete MRG15 from neonatal cardiomyocytes and evaluate changes in the regenerative capacity of cardiac progenitor cells and cardiomyocytes. They also administered a gene delivery vector to reactivate MRG15 and observed whether this could restore cardiomyocyte regeneration and repair.

Through multiple analyses, including histopathological examination, cell proliferation assays and echocardiographic functional assessments, the researchers found that deletion of MRG15 in neonatal mice significantly reduced cardiomyocyte proliferation and impaired regenerative capability. Likewise, removal of CD4+ Treg cells also suppressed cardiac regeneration. Importantly, reactivation of MRG15 using a gene delivery vector substantially restored regenerative function even in the absence of CD4+ Treg cells. These findings demonstrate a close functional link between CD4+ Treg cells and MRG15: CD4+ Treg cells promote cardiomyocyte proliferation and cardiac regeneration by regulating MRG15 expression. In other words, MRG15 serves as an essential mediator for CD4+ Treg cells to function, and both are indispensable for effective cardiac repair.

Neonatal CD4+ Treg cells can coordinate cardiac repair and regeneration

The researchers have also successfully uncovered the pathway through which CD4+ Treg cells regulate MRG15, thereby activating regenerative mechanisms. Experiments showed that within one week of cardiac injury, CD4+ Treg cells in neonatal mice secreted specific factors that induced MRG15 to form a complex with proteins such as TIP60, p300 and RNA polymerase II. This complex then activated cyclin D1 (also known as Ccnd1), a gene that controls cell division, promoting cardiomyocyte proliferation and repair.

(From left) Professor Kathy Lui Oi-lan from the Department of Chemical Pathology at CU Medicine; Mr Hou Yangfeng, a PhD student from the department, Photo source: CU Medicine

Mr. Hou Yangfeng, the first author of the study and a PhD student from the Department of Chemical Pathology at CU Medicine, commented: “This study is the first to elaborate how CD4+ Treg cells initiate the regeneration mechanism in neonatal cardiomyocytes by inducing MRG15 in conjunction with TIP60 and Ccnd1. Adult CD4+ Treg cells, however, lack this inductive capacity, suggesting that the quantity, function and distribution of these cells, and how gene expression is remodelled, may be the key reason behind the loss of regenerative potential in adult hearts, shedding new light on research into immunoregulation and cardiac regeneration.”

The corresponding author, Professor Kathy Lui Oi-lan from the Department of Chemical Pathology at CU Medicine, remarked: “From an immunological perspective, we have successfully unlocked the ‘key’ to and the underlying mechanism of neonatal cardiac self-repair, enhancing the world’s understanding of CD4+ Treg cells. These immune cells are not only the ‘peacekeepers’ of the human immune system but also act as ‘repair crews’ in the process of cardiac repair. Next, we will explore how this unique mechanism can be translated into clinical therapeutic strategies, with a view to developing innovative immune cell therapies for patients with myocardial infarction and heart failure.”

CU Medicine Hong Kong, Photo source: CU Medicine

Without cutting duodenal sphincter, the wireless microrobot can squeeze in narrow bile duct, wrap non-invasively the gallstone and take it out of the patient. This is the minimally invasive gallstone surgery achievable in the future.

Developed by Professor Zhang Li’s Lab in the Department of Mechanical and Automation Engineering at CUHK’s Faculty of Engineering, this liquid-bodied, magnetically controlled robot, dubbed the "Slime Robot", mimics the softness, high deformability, and viscoelasticity of Venom. The team aims to developing it as Super Medical Robot in the future.

The magnetic-controlled liquid robot developed by Professor Zhang Li's team at the Chinese University of Hong Kong is also known as a "slime" robot due to its strong deformability. Photo by Bastille Post

“We hope our microrobot can assist doctors to complete high difficulty task, and develop it as Super Medical Robot, ”Professor Zhang Li says when accepting exclusive interview with Bastille Post.

Professor Zhang Li, Department of Mechanical and Automation Engineering at CUHK’s Faculty of Engineering. Photo by Bastille Post

As early as in 2022, Zhang Li’s team unveiled Slime Robot successfully, which is mainly made of dynamic cross-linked magnetic hydrogel, used robotic arm to manipulate permanent magnet to control routes of the robot, cooperated with medical imaging equipment to track it.

Zhang Li notes, the prototype of Slime robot is Amoeba limicoline, which can transform into any shapes.

Early this year, the team developed the globally first antibiofilm liquid-bodied magnetic-controlled robot on the foundation of Slime robot. Zhang Li’s team planned to use Slime robot to fetch foreign bodies in stomach.

However, they found it cannot work out since the stomach acid would corrode the robot, so they shifted focus toward to antibiofilm.

“During the process of implanting devices into human bodies, sometimes it might bring bacteria, which will become biofilm that is difficult to remove after reproduction,” Zhang Li explains, “The research also finds that over 70 or 80 percent of chronic infection inside the body is due to biofilm, that is why we chose it as future direction.”

Zhang Li also hopes Slime robot can be used in minimally invasive gallstone surgery. To reach the narrow bile duct to do surgery, doctors currently use endoscopy which is of great difficulty. Therefore, Zhang Li’s Lab designs to make use of Slime robot’s strong deformation ability to enter the bile duct, wrap the gallstone and take it outside. Since the robot uses wireless control system, it is more flexible, the surgery wound can be smaller.

“This is a very wild idea,” Zhang Li laughs.

The "slime" robot can wrap around and remove foreign objects through narrow pipes. Photo by Bastille Post

Using Slime robots to remove biofilm infection on bile duct has been tested successfully on pig sample. Zhang Li hopes, the future clinic trial can be done in Hong Kong.

“One of the biggest advantages of Hong Kong is being backed by motherland, which means we can share multiple resources with other cities in the Greater Bay Area.” Zhang Li points out that starting the first human trial is an important task for them.

Zhang Li points out that the "Slime" robot's autonomy is between Level 1 and Level 2, meaning the robot can perform simple route planning and follow the path to its destination. Photo by Bastille Post

Since Slime robot can finish the tasks that are difficult for current minimally invasive robots, some local hospitals already expressed interest toward the project.

However, the medical community still holds concerns to the wireless control system of the robot.

“Traditional wire robots are more controllable when moving inside human body,” Zhang Li says, “some hospital worries that once it loses control inside human body, it is hard to get it back.”

In response to this, Zhang Li holds a 3S slogan when developing microrobots, which is Smaller, Smarter and Safer. His team also develops backend control system of microrobot to benefit the practical operation under commercialized scenarios.

In addition to the Slime robot, Zhang Li’s team has also developed a bionic microrobotic swarm inspired by swarm behavior patterns, which can similarly be navigated via magnetic fields.

Peng Yusong, a PhD student in Zhang Li’s research group, explained that the microrobotic swarm is designed for vascular interventional therapy and has already been successfully tested on human placental samples. For instance, during the treatment of cerebral aneurysms, the microrobotic swarm can assist in embolizing the aneurysm to prevent blood flow impact, thereby reducing the risk of rupture and hemorrhage.

Zhang Li's team developed a swarm of biomimetic micro-robots inspired by bee swarm behavior. Photo by Bastille Post

A schematic diagram of a swarm of biomimetic microrobots used in vascular interventional therapy. Provided by Peng Yusong, a PHD student in Zhang Li's research team

Zhang Li’s team has long engaged in extensive collaborations with prominent international research groups. As early as 2017, they established the "Joint Research Center for Innovative Medical Technology" together with Daegu Gyeongbuk Institute of Science and Technology (DGIST) in South Korea and ETH Zurich in Switzerland, to advance research and development of micro- or nanorobots, along with other nanotechnology applications for the diagnosis and treatment of gastrointestinal and cardiovascular diseases.

In 2020, with support from the Hong Kong government and led by The Chinese University of Hong Kong (CUHK), the team partnered with ETH Zurich, Imperial College London, Johns Hopkins University, and the Technical University of Munich to establish the Innovation Centre for Medical Robotics at Hong Kong Science Park. Serving as a collaborative platform, the center facilitates the translation of innovative biomedical engineering research into practical medical applications.

Medical Robotics Center. Image from the website