Salamanders and Stem cells:
the key to unlocking patient-specific therapies

By Amanda Chase, PhD

February 11,2020

Have you ever wondered why lizards can regenerate their tails after they drop them? How do salamanders have this amazing ability to regrow entire limbs and regenerate parts of major organs, including, for example, the heart? They stand out as the only vertebrates that can replace complex body parts that are lost or damaged at any age, meaning they have the ability to teach us an enormous amount about  regeneration, which could eventually be used for tissue repair in humans. Recently, it was shown that specialized immune cells, called macrophages, are critical in the early stages of limb regeneration in salamanders. Interestingly, macrophages also play a vital role in organ and tissue development in mouse embryos, producing small signals to promote growth of new limbs and heal wounds.

Humans, for the most part, lack this fantastic ability to regrow or regenerate major organs. But what if the right environment could be created to facilitate regrowth or regeneration. This would necessarily require a “super factor” to facilitate multiple changes and provide the energy needed for regeneration. There are clues as to what that factor could be, although it is not yet known. The innate immune system, an ancient pathway known to precede the evolution of adaptive immunity and being the first line of defense protecting the host from infectious microorganisms, has recently been shown to be a key player for this regrowth and regeneration. These “first responders” can be leveraged for transdifferentiation, i.e., the ability of one mature cell to transform into a different mature cell, and for nuclear reprograming, i.e., the process of changing identity of a specialized cell. Perhaps part of this innate immune response could act as such a factor, similar to macrophages in salamander limb regeneration.

Intriguing work from Stanford researchers, led by Nazish Sayed, MD, PhD, suggests that hypoxia-inducible factor one (HIF1a) is an unexpected but crucial regulator of innate immune-mediated nuclear reprograming. HIF1a has the potential to be this “super factor” that could facilitate reprograming in humans. This work will be published in Stem Cell Reports. Indeed, HIF1a was recently identified as a factor that regulates oxygen-dependent responses, and for this, William Kaelin, Jr., Sir Peter Ratcliffe, and Gregg Semanza were awarded the Nobel Prize in Physiology or Medicine for 2019. Piggybacking off that seminal work, it was found that HIF1a is a master regulator for the cellular response to low oxygen condition, and its function is necessary for immune function and wound healing. Given the link between HIF1a and the immune response, which is known to be involved in repair and regeneration, the Stanford group of researchers investigated the role of HIF1a in innate immune-dependent nuclear reprograming. They showed that HIF1a does this by initiating a switch in the way cells use energy to enable faster growth of induced pluripotent stem cells (iPSCs). This provides a key missing link in the knowledge that activation of the innate immune system is required for nuclear reprograming. This knowledge can help better understand how cells reprogram and tissue regeneration leading to safer, improved iPSC technology that can be used in clinical trials and lead to improved therapeutic strategies.

Nazish Sayed, MD, PhD