Making more supply to meet the demands of muscle cell therapy

If cancer is a disease of overabundance, where cells divide without restraint and tumors grow despite the body’s best interests, then degenerative diseases are disorders of deprivation.

When malfunctions occur in the biological machinery our muscles or our brains use for renewal and repairs, these tissues gradually wither. This kind of decline is the hallmark of diseases such as Alzheimer’s disease or Duchenne muscular dystrophy.

Scientists have long sought to develop treatments that enhance the muscle’s self-renewal capabilities to stave off degeneration. The use of this approach—known as regenerative medicine—for skeletal muscle degeneration has presented scientists with sizable hurdles.

Researchers have found it challenging to generate an adequate supply of therapeutic cells. These cells also tend to be immature, which limits their regenerative potential.

Scientists at Sanford Burnham Prebys Medical Discovery Institute published findings October 30, 2025, in Stem Cell Reports demonstrating a new method that yields up to twice as many therapeutic cells as previous protocols, while also delivering more mature and effective cells. This marks an important step in advancing regenerative medicine treatment for Duchenne muscular dystrophy and other degenerative muscle diseases.  

“In the case of Duchenne muscular dystrophy, you have a tissue that is diseased because it's lacking a fundamental protein,” said Alessandra Sacco, PhD, dean of the institute’s  Graduate School of Biomedical Sciences and professor in the Center for Cardiovascular and Muscular Diseases. “The overall objective is to develop a regenerative medicine treatment with healthy, fully functional stem cells, so that you are able to replace the diseased tissue with healthy tissue, completely correcting the disease.”

The cells Sacco and her team focused on in this new study are called skeletal muscle progenitor cells. These cells descend from stem cells and are primed to develop into more mature, specialized muscle cells to repair tissue damaged by normal use or injury.

“Generating enough of these myogenic cells is a critical bottleneck affecting a variety of applications,” said Luca Caputo, PhD, a postdoctoral associate at Sanford Burnham Prebys and the lead and co-corresponding author of the manuscript. “These include modeling muscular diseases in a petri dish, screening for new potential drugs and cell-based regenerative therapies.”

To learn how to clear this bottleneck with a greater yield of progenitor cells, the research team blocked the activity of Janus kinase 2 (JAK2), a signaling protein identified by the scientists in prior studies due to its effects on muscle stem cells.   

“We know that JAK2 is part of a classic pathway in which its signals activate another protein called signal transducer and activator of transcription 3, or STAT3,” said Sacco. “We previously observed that temporarily blocking this pathway enables muscle progenitor cells to expand in mice, so we wanted to test this in human cells.”

The scientists modulated JAK2 in embryonic stem cells and induced pluripotent stem cells made from samples provided by patients with Duchenne muscular dystrophy.

“We saw about a twofold increase in the yield of muscle progenitor cells,” said Sacco. “We then transplanted the cells into a mouse, and we saw that they were functional and contributed to tissue repair.”

Afterwards, the research team examined the maturation level of the resulting cells.

“Usually, when you generate cells from induced pluripotent stem cells or human embryonic stem cells, these cells are immature or embryonal,” said Caputo. “They are not the same cells that a developed human being will have in their body, and they need to mature in order to be more functional for use in regenerative medicine.”  

 In addition to generating about twice as many progenitor cells, the scientists found that inhibiting JAK2 pushed these cells from an embryonal stage to a late fetal or neonatal stage.

“We showed in mice that these more mature cells are more potent for muscle regeneration,” said Sacco. “With greater potency, we anticipate that you need fewer cells to treat a single patient.

“By combining increased yield and potency, more patients could be treated with each preparation of these cells, which will be important for one day making a treatment that is accessible to as many patients and families as possible.”

More research is needed to make regenerative medicine a safe and effective option for patients with Duchenne muscular dystrophy or other degenerative diseases. This includes understanding how to best deliver cell therapy into patients’ muscles. A new clinical trial derived from studies by Dr. Rita Perlingeiro’s group at the University of Minnesota opened this year to test the safety and tolerability of local injections.

The Sanford Burnham Prebys research team recognizes the need to continue improving the process for generating muscle progenitor cells and understanding what governs their maturation.

“We are going to fully refine the molecules that we can use to inhibit JAK2 signaling,” said Caputo. “This should help us generate more cells and cells that are closer to a postnatal, perinatal stage.”

“We also see opportunities on the fundamental research side to better understand the molecular cues that are driving the maturation of progenitor cells,” said Sacco.

“This will improve how we generate and test these therapeutic cells, as well as enable us to apply our findings more broadly to other degenerative diseases.”

Additional authors include:

• Cedomir Stamenkovic, Matthew T. Tierney, Alessandra Cecchini, Monica Nicolau, Gabriele Guarnaccia, Jesus R. Barajas and Pier Lorenzo Puri from Sanford Burnham Prebys
• Maria Sofia Falzarano and Alessandra Ferlini from the University of Ferrara
• Rhonda Bassel-Duby and Eric N. Olson from the University of Texas Southwestern Medical Center

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of General Medical Sciences, California Institute for Regenerative Medicine, European Reference Network for Rare Neuromuscular Diseases, Muscular Dystrophy Association and Italian Duchenne Parent Project.

The study’s DOI is 10.1016/j.stemcr.2025.102692.