MDI Biological Laboratory
Regeneration

Murawala Lab Discovers a New Stem Cell

  • February 16, 2024

Globe-spanning research project opens new possibilities for regenerative medicine  

In groundbreaking research published as a preprint in BioRxiv, MDI Biological Laboratory’s Prayag Murawala, Ph.D., and coauthors signal the discovery of a novel type of stem cell that drives a unique kind of tissue regeneration.

The finding, Murawala says, has “striking” implications for the fast-growing field of regenerative medicine, which aims to restore human health by regenerating or reengineering damaged cells, tissues and organs.

“Most regenerative activities we know depend on biological processes that mirror the way an embryo initially develops, but we show that in this case something quite different is going on,” Murawala says.

Side view of an axolotl tail, with fluorescently marked asomitic stem cells

Side view of an axolotl tail, with fluorescently marked asomitic stem cells snaking from top to bottom. MDI Bio Lab graduate student Sofia-Christina Papadopoulos pinpointed the novel stem cell’s location and distribution between the highly regenerative salamander’s muscles and tendons, using a gene-marking staining system called in-situ hybridization.

The discovery stems from long-term explorations by Murawala and colleagues of a remarkable salamander called the axolotl, which has extraordinary abilities to regenerate tissue, limbs and organs. Murawala is a global innovator in the development of the axolotl as a model for human health.

The research effort reaches back more than 10 years to his post-doctoral fellowship in the laboratory of regeneration pioneer Elly Tanaka, Ph.D., at Vienna’s Research Institute of Molecular Pathology. The institute is an incubator for emerging talent in the field – including Murawala’s co-lead on the new stem-cell finding, Wouter Masselink, Ph.D. (Tanaka is also a co-author).

The team has now shown that when an axolotl regenerates a lost tail it does not, as might be expected, redeploy the initial developmental pathways seen in an embryo as it constructs a tail. Instead, a new kind of stem cell that lurks at the at the border between muscles and tendons goes into action.

They call it an “asomitic” stem cell, in contrast to the already well-described “somitic” stem cell that is at work during the earliest developmental stages. “In the context of evolution, this is the first time it’s been shown that this type of stem cell exists,” Murawala says.

The discovery is rooted in some basic explorations in comparative and developmental biology among vertebrate animals. Research has demonstrated that from fish to salamanders to humans, an embryo’s development depends on the emergence of “somites”, relatively amorphous groupings of cells that are early precursors to the construction of bone, muscle and skin.

The somites’ activities are timed and patterned by a biological mechanism called the “somitic clock”,  which orchestrates the oscillating formation of somites along the length of the spine, laying out the developing tail’s musculoskeletal architecture, including a series of segmented vertebrae.

Using transgenic axolotl to manipulate the genes and proteins that run that biological clock, the researchers found that when they remove a gene that’s essential to its operations during embryonic development, a malformed tail would result. Yet if they amputated that first tail, the animal’s second try was a success, despite the lack of a clock to set a rhythmic pattern for vertebra formation.

“So during this regeneration process, they corrected their vertebra defects,” Murawala says. “That gave us an indication that physical somites and a somitic clock are required for development, but are not necessary for tail regeneration.”

That finding set the researchers on the trail that would lead them to the “asomitic” stem cell. Their investigative tools included microscopy by Marko Pende, Ph.D., who is a post-doctoral fellow in Murawala’s lab, and detective work by laboratory graduate student Sofia-Christina Papadopoulos, who used marker genes to visualize the new stem cells’ location, hidden inside bundles of muscle.

“These resident, asomitic stem cells that we found in regenerated tails have a potential to give rise to several types of tissue that is similar to somitic progenitors that are activated during embryonic tail development,” Murawala says. “But at the same time, they have a very different gene signature; they definitely are not the same population of cells, they are a different population.”

The decade-long, innovative research enterprise demonstrates the investment of time, dedication and access to state-of-the art resources needed to answer fundamental questions about development and regeneration. But they are the foundation for building therapies that can transform human health.

“Probably axolotl and even some fish can regenerate because they have these asomitic stem cells, but mammals cannot regenerate because they lack them,” says Murawala. “One future possibility in terms of regenerative medicine would be to make equivalent cells in the lab and graft them into a mammal. Then one can look at whether those cells can improve the body’s initial response to tissue damage and injury.”

More research is needed to understand just what is going on during an axolotl’s regeneration of a tail, Murawala says. He plans now to chart how the asomitic stem cells are set aside inside the muscle, and how they maintain their “multi-potent” ability to give rise to several different types of tissue once they are needed.

MDI Bio Lab president Hermann Haller, M.D., says the findings demonstrate the strength of the Lab’s modus operandi; using distinctive organisms for comparative studies that can transform the science of human health.

“Dr. Murawala has discovered novel stem cell functions and describes for the first time a mechanism in regeneration that changes the way we understand how spinal systems and vertebrae may recover from injury,” Haller says. “This is groundbreaking work in the field of regeneration.”