Wiring pain to repair: Dr Yen-Zhen (Angel) Lu’s DECRA backed quest to help tissues heal

Some wounds never heal.

For people living with diabetes or vascular disease, chronic ulcers can last for months or years. Even when there is no cure, these wounds still need to be cleaned, dressed and monitored to prevent infection and amputation. It is painful, time consuming and expensive, and there are still very few options to actually improve healing.

This is the challenge driving Dr Yen-Zhen “Angel” Lu, Senior Research Fellow at Monash University’s Australian Regenerative Medicine Institute (ARMI). Her publication in Nature paper in 2024 revealed a previously unknown “neuro-immune tissue regenerative axis” that connects sensory neurons, immune cells and tissue healing. Now, with an ARC Discovery Early Career Researcher Award (DECRA) — a national fellowship that supports outstanding early career scientists — she is turning that discovery into a deeper understanding of how our bodies trigger sensory neuron activation after injury, and whether this in turn drives tissue repair through immunomodulation.  She hopes findings in this project will help our bodies repair themselves more effectively. 

“Receiving a DECRA is a big step in building my independence as a researcher,” Angel says. “It gives me the chance to build my own research program and move closer to leading my own group. For me, this marks a very important transition to an independent researcher.”

Before Angel’s Nature study, scientists knew immune cells were crucial for regulating wound healing and tissue repair, but not how to control their behaviour in a precise and targeted way.

“We have known that immune cells are important for healing,” she says. “In chronic wounds, like diabetic wounds, dysfunctional immune cells are one of the leading causes of delayed healing. But we did not know how to regulate that immune response when it goes out of control.”

Her work showed that pain-sensing neurons, called nociceptors, are not just passive detectors of injury or more generators of pain.

“We usually think of nociceptive sensory neurons that detect noxious stimuli and convey pain signals to the brain,” she explains. “We realised they actually play an important role in controlling the immune response during tissue healing.”

In mouse models of skin and muscle injury, Angel and her colleagues selectively removed a specific subset of nociceptors. When those neurons were missing, skin wounds closed more slowly and damaged muscle regenerated poorly. They further found that, when the neurons were present, their nerve endings actively grew into the injured area and clustered in the granulation tissue that forms during repair.

The team then used immunostaining to reveal that these nerve endings were not only presented  in injury area, but also expressed high levels of the neuropeptide,Calcitonin Gene-Related Peptide (CGRP).

“These nerves penetrate into the injury site and start to express CGRP,” Angel says. “This peptide acts on immune cells and helps shift them into a pro-healing state.”

The result was a double breakthrough. Angel and her colleagues uncovered a new mechanism explaining how nerves and immune cells cooperate to drive repair, and she identified a tangible therapeutic target.

“By showing that CGRP can promote healing, we not only discovered a mechanism, but also identified future therapeutic targets,” she says. “Chronic wounds place a heavy burden on patients and health systems, and there is still no good solution for many of them. This gives us a new way to think about treatment.”

The DECRA project builds directly on that discovery.

“In our previous work, we saw these nerves growing into the injury site, but the pattern was very specific,” Angel explains. “They do not just sprout everywhere. They cluster in the middle of the injured area. That tells us there must be mechanisms controlling where they grow and how they are activated.”

The central question now is: How do nociceptors know when and where to extend their axons and release healing signals?

Angel’s DECRA will explore how myeloid cells, particularly neutrophils and macrophages, help switch on and organise this nerve response during tissue healing. Her hypothesis is that immune cells and neurons form a positive feedback loop in response to tissue injury: immune cells act as early responders that help drive sensory nerve outgrowth and activation, and activated neurons  in turn fine-tune immune responses to repair tissue.

“I want to identify the key molecular triggers that activate sensory neurons during tissue healing,” she says. “If we can pinpoint those factors and show they matter across different injury models, we can start thinking about new therapies that engage this pathway in a very controlled way.”

Over the next three years she will use mouse models of skin and muscle injury, together with single cell RNA sequencing and spatial transcriptomics, to define how myeloid cells influence nociceptor growth and function identify factors that trigger nociceptor activation and test how deleting these factors affects healing after injury.

“If in three years we can identify a key trigger for sensory neuron activation in tissue healing, and show it works across models, that would be a very big step,” she says.

Angel is already thinking about translation, particularly for people with diabetes who often have reduced sensory nerve function and chronic, hard to heal wounds.

“In diabetes, patients often develop neuropathy. They lose sensory neurons in their limbs, and that contributes to poor wound healing,” she says. “The group that will benefit most from this work are people whose nerves cannot do this job anymore. We want to mimic what the nerves would normally do by using neuropeptides directly as “molecular hooks” to promote tissue healing.In clinically relevant models of diabetic chronic wounds, simply delivering CGRP is not enough.

“CGRP is a very small peptide,” Angel explains. “If we just deliver it into the wound, it disperses very quickly and we cannot maintain its effect at the injury site.” And if it spreads to other tissues, such as blood vessels around the brain, it could cause side effects like migraine

Working with biomaterials experts in the Martino lab, Angel and colleagues engineered a smarter version of the molecule: CGRP fused to an extracellular matrix binding domain.

“In an injury area, many extracellular matrix proteins are generated and remodelled,” she says. “If we combine CGRP with an extracellular matrix (ECM) binding domain, it is like adding a hook. When we deliver this engineered CGRP, it hooks onto the proteins in the wound.”

By anchoring CGRP directly to the tissue, the molecule stays where it is needed most.

“Our results showed that coupling CGRP to this ECM binding domain “hook” allowed it to be retained at the injury site much longer. In a mouse model of diabetic chronic wounds, this engineered CGRP restored tissue healing, promoting skin wound closure and muscle regeneration,” Angel says. “That way, even when sensory neurons are not fully functional, we can still activate the same pro-healing pathway using neuropeptides directly. 

Future studies will move into models that more closely mirror human biology and explore how this strategy might support wound healing in people with diabetes and in older adults whose tissue healing naturally declines with age.

Angel’s scientific story is woven around one central idea. Immune cells matter, but they never act alone.

Originally from Taiwan, she completed a Bachelor of Science, a Master of Science’ and worked as a research assistant there before moving to Australia for her PhD.

“As an undergraduate, I worked on how immune cells influence the brain after stroke,” she says. “My master’s focused on how immune cells affect intestinal inflammation, like IBD or IBS. During my PhD at ANU I studied how immune cells contribute to photoreceptor degeneration in the retina and how they play a pathological role in disease progression.”

Across these projects, she saw the same pattern. Immune cells can be both protective and harmful depending on the context and how they interact with neighboring cells

“My research principle is that immune cells are very important, but we cannot look at them in isolation,” she says. “We have to understand how they crosstalk with other cell types and contribute to the overall integrity or breakdown of a tissue.”

Her move to ARMI at Monash and the Martino lab allowed her to apply that philosophy in regenerative biology across skin, muscle, bone and heart, and to start thinking more concretely about translation.

Angel was originally drawn to clinical medicine and inspired by the simple satisfaction of seeing someone relax and smile after they had been helped. Science, for her, became a way to widen that impact.

“Before I chose research, I was interested in being a clinician,” she says. “I liked to see people looking better and more energetic when something we do genuinely helps their health, and I moved into science because I wanted my work to improve human health on a much broader scale.”

Monash, and particularly Professor Mikaël Martino’s lab, offered the translational environment she was looking for.

“What I really value about being in the Martino lab is that we are not just doing fundamental biology,” she says. “There is a strong culture of thinking about clinical translation, patents and collaborations with biotech. That is very motivating for me.”

She credits Mikaël’s mentorship as pivotal.

“If you share your goals with him, he helps you think more clearly about possible next steps,” she says. “He takes the time to listen and then offers guidance, for example thinking about a project from a new angle or building collaborations“.

For early career researchers, especially women in STEM navigating a competitive and sometimes opaque system, Angel’s advice is both pragmatic and encouraging.

“Believing in yourself is critical, even when the system makes that hard,” she says. “But confidence does not come from nowhere. Positive feedback is important to build it.”

Her suggestion is to actively seek out experiences that generate that feedback beyond your usual environment

“Try different opportunities, talk to people, go to conferences,” she says. “Apply for prizes and grants and give talks. These become evidence of your capabilities and help you keep going.”

She also encourages researchers to look beyond their immediate circle.

“You can get a lot of advice and mentoring, but it is very valuable to seek mentors outside your existing network,” she says. “People from different fields or institutions can help you think in new ways.”

Over the next three years, Angel’s DECRA will focus on identifying the key molecular triggers that activate sensory neurons in healing tissues, mapping how immune cells and nociceptors talk to each other across multiple models, and testing strategies to engage this axis therapeutically.

“If we can define the factors that switch on sensory neurons for healing, validate them in different tissues and models, and show that engaging this axis improves repair, that will be a significant step,” she says.

From experiments where deleting pain sensing neurons slows repair, to engineered neuropeptides designed to hook into injured tissue, Angel’s work is steadily redefining how we think about pain, nerves and healing.

It is also a powerful example of what a DECRA can offer at a pivotal career stage. It gives a talented early career scientist the independence to follow an idea from mechanism to potential medicine, and brings healthier futures closer for people living with chronic wounds and age related decline in tissue healing.

About ARMI
The Australian Regenerative Medicine Institute (ARMI), based at Monash University in Melbourne, is a world leader in regenerative biology and stem cell research. ARMI works at the frontier of science, translating discovery into hope for people living with conditions like cancer, arthritis, and neurological injury.

Media Contact:
Emma Burrows, Communication Consultant ARMI.
M: 0417431376
E: emma.burrows@monash.edu