The emergence of regenerative medicine and npj Regenerative Medicine

JAX Scientific Director Nadia Rosenthal in an image collage header

Recently, Professor and Scientific Director, JAX Mammalian Genetics Nadia Rosenthal, Ph.D., F.Med.SciInvestigates the role of genetic variation and the immune system in tissue repair, focusing on cardiovascular and skeletal muscle diseaseNadia Rosenthal, Ph.D., F.Med.Sci., stepped aside as editor-in-chief of npj Regenerative Medicine, a journal she launched five years ago. Her tenure saw rapid growth for the journal, as well as in the field of regenerative medicine as a whole. After wrapping up her final issue, she reflected on her work with the journal, its bright future, and how a field that has been mostly theoretical—at least in terms of direct medical application—has progressed to the point that it now has great potential for profoundly affecting the clinical landscape in the years ahead

What led to the launch of npj Regenerative Medicine five years ago? Was there a particular advance, a new perspective on clinical utility, or was it simply time to provide a vehicle for papers specific to the field?

To realize this vision, I adopted a cross-disciplinary approach for systems-level discovery, with the goal of harnessing the natural powers of regeneration across the animal kingdom for healing and restoration in patients. ARMI soon became an international center for regenerative research.

In 2013 ARMI’s success caught the attention of the Nature journal family, which had recently launched its Partner Journal series, engaging active scientists in the editorial process. They approached me about starting a regenerative medicine journal as the topic was not represented by a high visibility platform. With Monash as the sponsoring institution, I assembled a small editorial board of top international scientists in the field and npj Regenerative Medicine was launched the next year.

What was the most rewarding part of editing npj Regenerative Medicine over the past five years?

In the life course of a journal, the founding editors have a unique set of challenges. To grow a journal from nothing requires a specific skill set, and a mix of faith, patience and stubbornness: at first, the pressure to publish anything is intense. In our first year npj Regenerative Medicine received 27 new submissions for the entire year, many of which I rejected. Nature’s editorial staff urged us to accept more papers, but I stuck to my guns. There were 46 total submissions in 2019, and 112 in 2020 with most submitted in the last half of the year.

Despite this modest start, our first impact factor (7.1) was announced in 2020, which recently grew to 10.364, with over 140 new submissions in the first half of 2021 alone, and the numbers and quality are increasing. I’m particularly proud of the reputation we have achieved in a relatively short time, now attracting around 20 new submissions every month. I’ve just signed on four brilliant young editors to handle the increased volume, and I am proud to say that they are sticking to the same standards and publishing only the highest quality research. The future is bright for the journal.

What are the largest current challenges in regenerative medicine research? What are the areas of greatest promise?

A popular view is that all emerging technologies disappoint in the short-term and over-deliver in the long term, and it will be another 20-30 years before the full clinical benefit of the field is realized. Currently, most regenerative medicine research remains confined to the bench rather than the bedside. Studying adult tissue turnover and replacement in an evolutionary context, using highly regenerative vertebrate species such as fish or salamander to analyze mechanisms of repair, has revealed how tissue regeneration proceeds in sequential phases of inflammation, tissue formation, and maturation involving a complex orchestration cell interplay with tissue-resident and recruited immune cells. In highly regenerative animals this scenario plays out in a timely fashion irrespective of tissue type, whereas in mammals a remarkable disparity exists between the regenerative capacity of various tissues and organs. For some organs where repair is an evolutionarily conserved feature (such as liver), insightful mechanistic experiments in other species can often be of immediate relevance in mammalian systems, whereas the regenerative capacity of other tissues, such as the heart or nervous system, vary widely across species, making comparative studies of particular interest for pinpointing blockades in the restoration of function.

Advances in regenerative medicine rely heavily on stem cells and tissue engineering. These strategies have had minimal impact on medicine so far, but recent advances in our basic knowledge of the pathology involved in tissue damage and regeneration have benefitted from remarkable progress in stem cell biology, so the prospect of clinically applied tissue repair strategies is a tangible reality.  Examples include the injection of stem cells or progenitor cells (cell therapies); the induction of regeneration by biologically active molecules administered alone or as a secretion by infused cells (immunomodulation therapy); and transplantation of organs and tissues grown in vitro (tissue engineering).

Alongside the efforts to elucidate the biology of transplanted cells, we need to understand how to provide the appropriate environment for the transplanted cells to successfully integrate and repair tissue. Within the context of a body, cells continually interact with other cells and the extracellular matrix that surrounds and physically supports them. Studies in embryonic development and adult tissues suggest that there is a tissue-specific niche that helps to control the proliferation and fate of resident stem cells. The niche is typically composed of supportive cells including macrophages, myofibroblasts and other immune cells. A defined extracellular matrix (ECM) is also typically found in a tissue stem cell niche. Together, these niche components help to promote appropriate tissue repair. In the setting of chronic organ injury, however, signals and cellular controls underlying replacement of healthy tissue are distorted. Thus the ‘niche’ is not as receptive to transplanted cells and does not supply normal trophic signals, providing an additional challenge.

These impediments notwithstanding, the potential for regenerative medicine to redress the increasing prevalence of degenerative diseases in a globally aging population has attracted huge scientific and public interest and support.

I am particularly excited about the role of immune cellular players in tissue repair. A rapid resolution of the pro-inflammatory phase and transition to the regeneration phase is crucial to the outcome of tissue damage and its dysregulation may aggravate complex diseases and prevent repair. Among the panoply of immune cells involved in the response to both acute and chronic wounds, recent findings have highlighted novel and often unexpected roles for select immune cell types for effective cell replacement and restoration of tissue integrity across the evolutionary spectrum. With a better understanding of the intimate relationship between immune components and the relevant tissues, assessment of circulating immune cells in recovering patients may provide additional clues to the extent of tissue damage and the progress of tissue regeneration Combining advances in immunotherapy with a deeper understanding of the genetic variation amongst efficient vs poor “healers” in the human population could help stratify patients and deliver real precision regenerative medicine.

What medical impact do you expect to see over the next decade? Do you think it will be feasible to regrow/regenerate certain human cells and tissues in the clinic?

Although our understanding the basic mechanisms of tissue repair is still far from complete, the rapid clinical translation currently occurring in regenerative medicine predicts an increasing number of ‘first-in-human’ tissue repair studies. Some common features include developing new cellular, acellular and molecular based treatments that enhance the body's own repair system; developing a cost effective and disease-specific source of cells needed to test the efficacy of compounds in the lab to speed up the process of drug testing; and constructing ex vivo small tissues comprising of one or several types of specialized cells.

Clinical tissue repair through the safe delivery of exogenous cells, be they stem cells or immune cells, entails a substantial degree of infrastructure. Implantation of composite tissues grown ex vivo would require a facility for cell growth and artificial biomaterials, as well as a clinical trials facility with regulatory permission, high resolution clinical imaging and access to molecular pathology level tissue analysis. This multi-disciplinary environment needed for the clinical delivery of regenerative therapies will engage clinical research centers with a broad focus on regenerative medicine or an existing transplant program. 

The role of the immune system in tissue regeneration may provide clues for intervening in tissue injury with small molecule approaches and biological agents such as cytokines. As with the treatment of human autoimmune and inflammatory diseases, assessment of the molecular differences between patient immune responses in traumatic or chronic injury settings may provide vital clues to the progression of disease and prompt the design of personalized therapies.