Stories that caught our eye: FDA grants orphan drug status to CIRM-funded therapy; stunning discovery upends ideas of cell formation; and how tadpoles grow new tails

Gut busting discovery

Intestinal stem cells: Photo courtesy Klaus Kaestner, Penn Institute for Regenerative Medicine

It’s not often you read the word “sensational” in a news release about stem cells. But this week researchers at the University of Copenhagen released findings that are overturning long-held ideas about the development of cells in our stomachs. So perhaps calling it “sensational” is not too big a stretch.

In the past it was believed that the development of immature cells in our stomachs, before a baby is born, was predetermined, that the cells had some kind of innate sense of what they were going to become and when. Turns out that’s not the case. The researchers say it’s the cells’ environment that determines what they will become and that all cells in the fetus’ gut have the potential to turn into stem cells.

In the “sensational” news release lead author, Kim Jensen, says this finding could help in the development of new therapies.

“We used to believe that a cell’s potential for becoming a stem cell was predetermined, but our new results show that all immature cells have the same probability for becoming stem cells in the fully developed organ. In principle, it is simply a matter of being in the right place at the right time. Here signals from the cells’ surroundings determine their fate. If we are able to identify the signals that are necessary for the immature cell to develop into a stem cell, it will be easier for us to manipulate cells in the wanted direction’.

The study is published in the journal Nature.                             

A tale of a tail

African clawed frog tadpole: Photo courtesy Gary Nafis

It’s long been known that some lizards and other mammals can regrow severed limbs, but it hasn’t been clear how. Now scientists at the University of Cambridge in the UK have figured out what’s going on.

Using single-cell genomics the scientists were able to track which genes are turned on and off at particular times, allowing them to watch what happens inside the tail of the African clawed frog tadpole as it regenerates the damaged limb.

They found that the response was orchestrated by a group of skin cells they called Regeneration-Organizing Cells, or ROCs. Can Aztekin, one of the lead authors of the study in the journal Science, says seeing how ROCs work could lead to new ideas on how to stimulate similar regeneration in other mammals.

“It’s an astonishing process to watch unfold. After tail amputation, ROCs migrate from the body to the wound and secrete a cocktail of growth factors that coordinate the response of tissue precursor cells. These cells then work together to regenerate a tail of the right size, pattern and cell composition.”

Orphan Drug Designation for CIRM-funded therapy

Poseida Therapeutics got some good news recently about their CIRM-funded therapy for multiple myeloma. The US Food and Drug Administration (FDA) granted them orphan drug designation.

Orphan drug designation is given to therapies targeting rare diseases or disorders that affect fewer than 200,000 people in the U.S. It means the company may be eligible for grant funding toward clinical trial costs, tax advantages, FDA user-fee benefits and seven years of market exclusivity in the United States following marketing approval by the FDA.

CIRM’s President and CEO, Dr. Maria Millan, says the company is using a gene-modified cell therapy approach to help people who are not responding to traditional approaches.

“Poseida’s technology is seeking to destroy these cancerous myeloma cells with an immunotherapy approach that uses the patient’s own engineered immune system T cells to seek and destroy the myeloma cells.”

Poseida’s CEO, Eric Ostertag, said the designation is an important milestone for the company therapy which “has demonstrated outstanding potency, with strikingly low rates of toxicity in our phase 1 clinical trial. In fact, the FDA has approved fully outpatient dosing in our Phase 2 trial starting in the second quarter of 2019.”

Keeping intestinal stem cells in their prime

Gut stem cells (green) in the small intestine of a mouse.

The average length of the human gut is 25 feet long. That’s equivalent to four really tall people or five really short people lined up head to toe. Intestinal stem cells have the fun job of regenerating and replacing ALL the cells that line the gut. Therefore, it’s important for these stem cells to be able to self-renew, a process that replenishes the stem cell population. If this important biological process is disrupted, the intestine is at risk for diseases like inflammatory bowel disease and cancer.

This week, Stanford Medicine researchers published new findings about the biological processes responsible for regulating the regenerative capacity of intestinal stem cells. Their work, which was partially funded by CIRM, was published in the journal Nature.

Priming gut stem cells to self-renew

Scientists know that the self-renewal of intestinal stem cells is very important for a happy, functioning gut, but the nuances of what molecules and signaling pathways regulate this process have yet to be figured out. The Stanford team, led by senior author and Stanford Professor Dr. Calvin Kuo, studied two signaling pathways, Wnt and R-Spondin, that are involved in the self-renewal of intestinal stem cells in mice.

Dr. Calvin Kuo, Stanford Medicine.

“The cascade of events comprising the Wnt signaling pathway is crucial to stem cell self-renewal,” Dr. Kuo explained in an email exchange. “The Wnt pathway can be induced by either hormones classified as “Wnts” or “R-spondins”.  However, it is not known if Wnts or R-spondins cooperate to induce Wnt signaling, and if these Wnts and R-spondins have distinct functions or if they can mutually substitute for each other.   We explored how Wnts and R-spondins might cooperate to regulate intestinal stem cells – which are extremely active and regenerate the 25-foot lining of the human intestine every week.”

The team used different reagents to activate or block Wnt or R-spondin signaling and monitored the effects on intestinal stem cells. They found that both were important for the self-renewal of intestinal stem cells, but that they played different roles.

“Our work revealed that Wnts and R-spondins are not equivalent and that they have very distinct functions even though they both trigger the Wnt signaling cascade,” said Dr. Kuo. “Both Wnts and R-spondins are required to maintain intestinal stem cells.  However, Wnts perform more of a subservient “priming” function, where they prepare intestinal stem cells for the action of R-spondin, which is the active catalyst for inducing intestinal stem cells to divide.”

The authors believe that this multi-step regulation, involving priming and self-renewal factors could apply to stem cell systems in other organs and tissues in the body. Some of the researchers on this study including Dr. Kuo are pursuing this idea through a new company called Surrozen, which produces artificial bioengineered Wnt molecules that don’t require activation like natural Wnt molecules. These Wnt molecules were used in the current study and are explained in more detail in a separate Nature article published at the same time.

The company believes that artificial Wnts will be useful for understanding stem cell biology and potentially for therapeutic applications. Dr. Kuo explained,

“The new surrogate Wnts are easily produced and can circulate in the bloodstream, unlike natural Wnts.  There may be medical applications of these bioengineered Wnt surrogates in stimulating various stem cell compartments of the body, given the wide range of stem cells that are governed by natural Wnts.”