New Strategy Developed at UCLA Generates Functional Muscle Cells from Stem Cells in DMD Mice

New Strategy Developed at UCLA Generates Functional Muscle Cells from Stem Cells in DMD Mice

UCLA researchers have developed a new method to efficiently produce and transplant functional skeletal muscle cells from human pluripotent stem cells (hPSCs). This may offer new therapeutic opportunities for patients who have muscle diseases such as Duchenne muscular dystrophy (DMD).

The findings were reported in an article titled “ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs” that appeared in the journal Nature Cell Biology.

Pluripotent stem cells are immature cells that have the potential to become virtually any cell type that we have in our bodies. This maturation process is tightly regulated, requiring very specific external stimulus at a certain time to make a particular type of cell.

Because of their great potential, the transplanting of hPSCs has been explored as a therapeutic option for a broad range of diseases. For muscular dystrophies, hPSCs represent a potential source of mature muscle cells to replace those that are deficient or lacking.

A research team led by April Pyle, associate professor of microbiology, immunology, and molecular genetics, and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, tested existing protocols for hPSC maturation and found they would give rise to muscle cells that were only partially functional compared to healthy, natural muscle cells.

“We have found that just because a skeletal muscle cell produced in the lab expresses muscle markers, doesn’t mean it is fully functional,” Pyle said in a news release.

To better understand the difference between hPSC-derived cells and natural muscle cells, the team conducted a comparative genetic profile analysis. With this strategy they found that two cell surface receptors (ERBB3 and NGFR) were found only in functional muscle cells, including in human natural muscle cell progenitors.

By using the hPSC maturation process, the team could specifically select and isolate hPSC-derived muscle cells that had the two surface markers. These cells were found to have improved efficiency in forming functional muscle fibers, but they still showed some traits that were different from those shown by natural muscle cells.

An additional genetic analysis revealed that the TGF-β signaling pathway was preventing the full maturation of hPSC-derived muscle cells.

To evaluate the therapeutic potential of these cells, the team used their optimized maturation protocol on hPSCs collected from a Duchenne MD patient. The cells had been manipulated using the CRISPR-Cas9 gene-editing technology to produce dystrophin – the protein that is lacking in Duchenne patients. The selected cells were then transplanted into mice that lacked dystrophin along with a TGF-β inhibitor.

With the combined therapeutic strategy, the transplanted cells efficiently developed into mature functional muscle cells. The hPSC-derived cells also showed increased levels of dystrophin protein near the levels to those found in healthy human muscle cells.

“The results were exactly what we’d hoped for,” Pyle said. “This is the first study to demonstrate that functional muscle cells can be created in a laboratory and restore dystrophin in animal models of Duchenne using the human development process as a guide.”

The team is planning to explore their hPSC isolation and maturation strategy to generate muscle cells that can provide long-term protection from injury.

“Furthering our understanding of human developmental myogenesis [muscle cell formation] will provide inroads to regenerative approaches for muscle diseases, including in combination with gene-edited patient-derived hPSCs,” the researchers wrote in the study.

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  1. Earl Clark says:

    This is awesome. So if crispr can go in and correct the genetic mutation, could this then maybe help the person’s muscle regain strength? Maybe helping the non ambulatory to maybe walk again?

    • Alice Melão says:

      Dear Early,
      In this study the researchers used CRISPR technology to modify the progenitor cells before they were transplanted. These cells would then form new muscle fibers. So, only the new fibers would have normal dystrophin levels, while the patient’s original cells would still have low levels. Independently of the involved mechanists, this new treatment protocol represents a potential way to regain muscle strength. Yet more studies are still necessary to confirm its potential in patients.

      • Earl Clark says:

        Thanks Alice. It’s so nice to open my email everyday and read something like this that keeps my hope for my child alive. I know one day soon that MD will be no more. Thanks again

  2. Sujit Jadhav says:

    I have been following these muscular dystrophy research news since 15-17 yrs. There is always news about big successes in labs or animals, which says are very promising.

    But when will be a news on success on humans ?

    • Asma imran says:

      Yes u said good words when kids wil be from DMD who is suffering…my son also is of 10 yr plz give good suggestions for great success….his age is10 yr whole life is front of my son ..he is not in a walking Position since from 1 n half yr …

      • Sujit Jadhav says:

        As a patient nothing is in our hands. Only GOD can help and guide us in this.

        Once the off-target obstacle is overcome in CRISPR-cas9 or an alternate option of base editing in CRISPR is verified comprehensively , GOD willing then there should be a treatment/cure soon.

        In the mean time, GOD willing I personally see good hope in GALGT2 surrogate gene therapy & also Exon-Skipping therapy.

        Scientists around world today know more about muscular dystrophy and are working very hard to get a fix.

        May Almighty GOD help & guide them find a cure.

  3. NESHA PERSAD says:

    Hi .I am from Trinidad my son is 15 and i cant wait for some good news..all i can do is pray for something come true..It’s heartbreaking to see them like that.

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