Fight Aging!

Is is now going on three decades since the first flush of excitement for regenerative medicine in the form of stem cell therapies. Unfortunately, producing meaningful, reliable regeneration with cell therapies turned out to be a great deal harder then hoped. It is still not a solved problem, outside a few narrow applications. In the intervening time, the field of regenerative medicine has expanded considerably beyond cell therapies, now of many varieties, to encompass approaches such as immune modulation and reprogramming native cell behavior. As today's commentary notes, there is still no magic button to turn on regeneration, but progress continues on what turned out to be a far harder challenge than first thought.

Emerging frontiers in regenerative medicine

Nearly every human malady, be it injury, infection, chronic disease, or degenerative disease, damages tissues. Moreover, 45% of all deaths can be traced to inflammation- and fibrosis-related regenerative failures. Restoring health after damage requires the answer to a key question: How can human tissues be coaxed to regenerate? Identifying instructive cues that direct refractory tissues down a regenerative path remains a critical yet elusive goal. Nonetheless, approaches to target roadblocks that impede regeneration, including insufficient and/or functionally inadequate progenitor cells, fibrosis, and chronic inflammation, are continuing to progress from bench to bedside. Pivotal advances have been made to overcome these hurdles using cell therapy, in vivo reprogramming, synthetic biology, and antifibrotic and anti-inflammatory therapies, but many challenges remain and knowledge gaps must be addressed to make regeneration a mainstay of modern medicine

The most conspicuous requirement for regenerative therapies is to replace the components of tissues that were lost or compromised by disease. Invigorating endogenous stem cells is an appealing strategy, but, to date, the greatest benefits have emerged from cell therapies. Adult stem cell-based regenerative therapies have shown clinical benefit to treat hematological malignancies, burn wounds, and ocular degeneration. Human pluripotent stem cell (hPSC)-based therapies have also shown promise and have entered clinical trials in the United States for type 1 diabetes, Parkinson's disease, and age-related macular degeneration. These three diseases are particularly amenable to stem cell-based therapies because they are associated with deficiency of a defined cell type.

Despite these early glimpses of success, cell therapies are hampered by many biological and technical hurdles. Autologous hPSC-based therapies derived from induced pluripotent stem cells (iPSCs) avoid immune aggravation, but this cost- and labor-intensive strategy requires safety testing for each use. A major concern with nonautologous cell therapy is immune rejection of the graft. Thus, "off-the-shelf" allogeneic therapies must be coupled to strategies that allow them to avoid rejection. Producing sufficient numbers of cells for engraftment has been successful in the skin but poses a major challenge for regenerating tissue in other organs, particularly if only a small proportion of cells survive after transplant.

An alternative approach to overcome the challenge of directing and integrating grafts in hard-to-reach internal organs is to repurpose cells that are present at the damage site by reprogramming them in situ with specific transcription factors. Reprogramming has been a particularly attractive strategy for the adult heart, which, unlike the embryonic heart, lacks bona fide progenitors. A subset of in vivo cellular reprogramming efforts are aimed at converting fibroblasts into cardiomyocytes to maintain cardiac function. Alternatively, transient expression of pluripotent transcription factors in adult cardiomyocytes induced proliferation, resulting in improved outcomes in adult mice after myocardial infarction.

In addition to replacing lost tissue with cell therapies and in vivo reprogramming, many injurious and complex disease states evoke inflammatory responses that must also be suppressed (see the figure). The state of the recipient tissue, often diseased, remains a challenging facet of applying cell therapies. New approaches to modulate inflammation include engineering stem cells with bioresponsive gene circuits that can sense inflammatory factors such as cytokines or reactive oxygen species and, in turn, induce the production of anti-inflammatory factors, allowing endogenous progenitors or transplanted cells to repair damage.

What was once considered the future of medicine is now becoming reality. But there is no magic pill for regeneration (yet). In addition to scientific and technological innovation, there are also practical considerations of cost and production. Achieving regeneration in humans will require a rapid transition from rodent models to clinically relevant large animal and human studies. Ascending the summit of human regeneration demands an interdisciplinary effort that brings together biologists, biomedical engineers, and clinicians. The view from the top will reveal a transformed medical landscape that is able to seamlessly rejuvenate organs, ultimately extending human life span and health span.