About author: Srinivas Allanki is from Eluru, Andhra Pradesh, India. He did his Bachelor’s and Master’s (Dual-Degree) in Biotechnology from the Department of Biotechnology at the Indian Institute of Technology Madras (IIT Madras). His Master’s research, under the joint supervision of Prof. Madhulika Dixit and Prof. Nandan Kumar Sinha, mainly focused on devising strategies to analyze and model transcriptomic data. After graduating from IIT Madras in 2016, he joined the research group of Dr. Sven Reischauer in the Department of Developmental Genetics led by Prof. Didier Stainier at the Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. The primary goal of his doctoral research is to identify and characterize the molecular mechanisms that orchestrate tissue regeneration in zebrafish, paving the way for potential therapeutic strategies in human regenerative medicine. He identified Interleukin-11 signaling as a global regenerative pathway in zebrafish that suppresses scar formation. This work was recently published in Science Advances. He currently continues to investigate the molecular and genetic consequences of Interleukin-11 signaling during regeneration and scarring after tissue damage, in Dr. Reischauer’s group in the Department of Experimental Cardiology, Justus-Liebig University Giessen, Giessen, Germany, which focuses on cardiac development and pathologies.
Interview Questions
How would you explain your research outcomes to the non-scientific community?
Injuries in humans typically lead to the formation of scars permanently impairing a given tissue’s function. This fibrotic scarring response is one of the main causes of various lethal human diseases, most prominently in the heart. Injury to the heart caused by a heart attack leads to a scarring response that hinders optimal cardiac performance. The cell types that mainly contribute to scarring are the so-called fibroblasts and endothelial cells, also known as the cells that make up connective tissue and form blood vessels, respectively. In response to injury, these cell types change into so-called myofibroblasts, which then deposit and control the maturation of the stiff and non-functional scar tissue.
Unlike humans, some vertebrates can almost completely regenerate damaged tissues, thus returning the lost tissue to its original healthy state. These species include many fish, most notably zebrafish, a tiny freshwater fish that lives in the Ganges river and its tributaries, and became one of the favorite model organisms to many fields of research. Bringing sci-fi movies to life, zebrafish can functionally restore amputated fins, scales, the central nervous system, and even internal organs, including the heart after injury within a few days to weeks. We first identified that the formation of myofibroblasts is very limited in these regenerative animals after heart injury. Finding the mechanisms that zebrafish employ to limit scarring would lead to potential regenerative therapies. In this study, we identify the Interleukin-11 (Il-11) signaling pathway as one such mechanism that promotes regeneration and limits scar formation in multiple zebrafish tissues, making it the first global regulator of regeneration discovered to date. In the zebrafish heart, we also show that Il-11 signaling in endothelial cells helps the regenerating heart muscle cells to migrate and repopulate the damaged area. Learning from this tiny fish, our findings open potential new avenues to enhance regenerative medicine in humans.
How do these findings contribute to your research area?
Rodents, like humans, form a permanent scar after heart injury and hence work as excellent models to study human diseases. Earlier research in rodents showed that injecting IL-11 protein after heart injury improved their cardiac health, suggesting that the IL-11 pathway limits fibrosis. Taking these findings ahead, as a preliminary clinical trial, researchers have even tried injecting IL-11 into human patients with heart conditions. In contrast to these findings, recent studies in rodents highlight that the IL-11 pathway drives fibrosis. These studies propose that using IL-11 blockers can mitigate fibrosis in human diseases. Altogether, these contradicting results in the rodent models leave the role of IL-11 in tissue fibrosis open to debate. Our data from the regenerative zebrafish model now add evidence that Il-11 indeed limits fibrotic scarring, and that the secrets of tissue regeneration potentially lie in the evolutionary differences downstream of IL-11 signaling, between regenerative and non-regenerative species.
What was the exciting moment during your research?
A couple of exciting moments actually. The first was when we discovered that zebrafish il11ra (Il-11 receptor) mutants do not regenerate their caudal fins and that we were targeting the right pathway! The second was when we got an answer for my most favorite question – is there crosstalk between endothelial cells and heart muscle cells downstream of Il-11 signaling in the regenerating zebrafish heart. We tried to rescue muscle cell migration in the heart in il11ra mutants by re-expressing il11ra specifically in the endothelial cells. This experiment was the trickiest and technically the most challenging of all. Given the wonderful odds (!) of successful experiments in research in general, I was prepared for yet another failed attempt. However, even before I fully processed and analyzed the samples, I took a brief look under the microscope and the curing effect was already visible! Days like these make us completely forget about all the hard work we put in.
What do you hope to do next?
We are currently following up on the cell-specific aspects of Il-11 signaling during regeneration, and digging deeper into the differences between mammalian and zebrafish Il-11 signaling. I am looking forward to tackling and solving some of the subcellular mysteries in Cancer Biology during my postdoctoral training shortly.
Where do you seek scientific inspiration from?
Dr. A.P.J. Abdul Kalam – a great man and a wonderful human being. One of his quotes that inspires me the most and is apt for every single day for the scientific community – “You should not give up, and we should not allow the problem to defeat us”.
How do you intend to help Indian science improve?
Scientific research – be it understanding the universe we live in or the universe that lives in us – I think, fascinates everyone no matter what. Its beauty is rightly celebrated when it can reach every nook and corner of the planet, beyond any humane boundaries. I realized this yet another time when I was explaining to my mother, how a viral infection takes place, how vaccines work and the decades of research that went into making them. The wonder in her eyes was priceless! Incidents like this only augment my desire to be a teacher someday and spread the knowledge to the next generation of scientists.
Reference
S. Allanki, B. Strilic, L. Scheinberger, Y. L. Onderwater, A. Marks, S. Günther, J. Preussner, K. Kikhi, M. Looso, D. Y. R. Stainier, S. Reischauer, Interleukin-11 signaling promotes cellular reprogramming and limits fibrotic scarring during tissue regeneration. Sci. Adv. 7, eabg6497 (2021).
Edited by: Ritvi Shah