Development of Innovative Regenerative Therapeutic Strategies by Translating Bacterial Ingenuity of Reprogramming and Organ Growth

Despite increased understanding of disease mechanisms and technological advances, we still lack both disease-modifying therapies for many chronic diseases and rejuvenating strategies to promote healthy aging. Our incomplete understanding of regenerative mechanisms is a barrier to developing pro-regenerative therapies to prevent or reduce damage and delay the decline in tissue function in chronic diseases, cancers, and aging. Organ-level tissue regenerative and rejuvenation approaches would represent the most effective strategies to restore function in damaged or aging organs. However, such approaches are not currently available; hence this is an unmet medical need with a societal impact.

The adult liver, with its multiple vital functions, has a profound inherent regenerative capacity and is the exemplary organ for studying such processes. Chronic liver diseases are estimated to cause 2 million deaths annually, but transplantation remains the only treatment. Due to declining liver functions, aging populations carry an inevitably high risk of developing liver diseases and cancers. Although native mechanisms that restore the prior liver mass and normal function after injuries have been intensively studied, no therapeutic strategies to leverage these mechanisms in chronic liver diseases and aging livers have been developed. Current approaches using traditional models have failed. Therefore, innovative approaches for developing effective organ-level regenerative and rejuvenating therapeutics are required.

We are beginning to unravel many secrets of human cell biology from studies of unconventional but evolutionarily refined natural models of bacterial co-optation of mammalian developmental and de novo regenerative pathways in adult tissues. In particular, strictly obligate intracellular bacteria with total dependence on host cell functions have mastered effective strategies to maintain both bacterial and host cell survival during their co-evolution with natural animal and human hosts. Therefore, we reasoned that understanding these bacterial micromanipulations would represent the necessary first step for developing therapeutic strategies to similarly manipulate host cell functions – translation of bacterial strategies evolved to promote host organ health to tackle human diseases and aging process. Previously, we demonstrated that the strictly obligate intracellular pathogen Mycobacterium leprae (ML) can reprogram adult tissue cells to stem cell/progenitor cells (Masaki et al., Cell 2013; Hess et al., Curr Opin Microbiol 2015). Building on this concept, most recently we have shown that during the establishment phase of in vivo infection in a natural animal host, nine-banded armadillos, ML promotes the de novo growth, regeneration, and rejuvenation of adult liver, bypassing inherent mechanisms that define normal organ size
without causing fibrosis or cancers (Hess et al., Cell Rep Medicine, 2022). Deciphering these safer mechanisms behind this bacterial ingenuity will provide insights to advance our understanding of the native regenerative machinery to permit the development of new organ re-growth therapeutic strategies. Further, such models may represent an innovative platform enabling the development of healthy aging and cancer preventive interventions. This presentation will describe our vision and potential approaches to this challenge.