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Developmental Biology - Cell Therapy

Therapy for Muscular Dystrophies

New Cell Replacement Therapies for Muscular Dystrophies...

The University of Minnesota Medical School is advancing cell replacement therapies with the promise of treating muscular dystrophy at the cell level.

The research published in Proceedings of the National Academy of Sciences of the United States of America (PNAS) allows authors Tania Incitti PhD, Post-Doctoral Associate, and Rita Perlingeiro, Professor, Department of Medicine at the University of Minnesota Medical School, to gain a deeper understanding of cells generated in vitro for muscle regeneration.

Perlingeiro's lab, over several years, pioneered the development of muscle stem/progenitor cells from pluripotent stem cells in vitro (a culture dish rather than in a human or animal). These cells are able to generate new functional muscle when transplanted into mice with muscular dystrophy. Critically, they also populate new muscle with new muscle stem cells also derived from pluripotent stem cells, which allows new muscle to repair itself if injured.

Now for the first time, researchers have identified the molecular signature of muscle stem cells generated in the petri dish. They have compared newly generated muscle stem cells that populated into newly formed muscle. They also compared these profiles to muscle stem cells isolated from mice at different developmental stages (1. embryonic, 2. fetal, 3. neonatal, and 4. adult).

Their results reveal that:
• Laboratory generated muscle cells are molecularly embryonic in structure
• Transplanted into live mice, these cells change molecular structure to resemble pre-existing neonatal and adult stem cells.
• This adaptation appears to be induced by association with existing healthy muscle cells - effectively 'repairing/replacing' damaged muscle cells.
"While the engrafted muscle stem cells did not look identical to adult muscle cells, they no longer looked like embryonic cells either. This tells us they are changing after transplantation into the muscle environment. Investigators also re-transplanted engrafted muscle stem cells and found very small numbers of those cells had potential for muscle regeneration upon a secondary transplant. We are now asking - What are the environmental cues changing our cells?"

Tania Incitti PhD, Post-Doctoral Associate, University of Minnesota Medical School.

"This study brings us more knowledge about the mechanism behind muscle cells' tremendous regenerative potential. We knew that new muscle stem cells were present after transplantation. But understanding what role the environment plays, understanding that cells are truly reshaped by exposure to muscle environment — is an exciting finding.

Knowledge at the molecular and functional level of what happens upon transplantation, is particularly important for future therapeutic applications."

Rita Perlingeiro, Professor, Department of Medicine, and member of the Lillehei Heart Institute, Stem Cell Institute, and Wellstone Muscular Dystrophy Center at the University of Minnesota Medical School..

These studies provide mechanistic insights into the nature of in vitro-generated iPSC-derived myogenic progenitors and what these cells become upon engraftment. The fact that iPSC-derived myogenic progenitors remodel their embryonic/fetal molecular signature upon in vivo exposure to the adult muscle environment has important implications for therapeutic applications, as attested by their robust and persistent regenerative potential.

Optimal cell-based therapies for the treatment of muscle degenerative disorders should not only regenerate fibers but provide a quiescent satellite cell pool ensuring long-term maintenance and regeneration. Conditional expression of Pax3/Pax7 in differentiating pluripotent stem cells (PSCs) allows the generation of myogenic progenitors endowed with enhanced regenerative capacity. To identify the molecular determinants underlying their regenerative potential, we performed transcriptome analyses of these cells along with primary myogenic cells from several developmental stages. Here we show that in vitro-generated PSC-derived myogenic progenitors possess a molecular signature similar to embryonic/fetal myoblasts. However, compared with fetal myoblasts, following transplantation they show superior myofiber engraftment and ability to seed the satellite cell niche, respond to multiple reinjuries, and contribute to long-term regeneration. Upon engraftment, the transcriptome of reisolated Pax3/Pax7–induced PSC-derived myogenic progenitors changes toward a postnatal molecular signature, particularly in genes involved in extracellular matrix remodeling. These findings demonstrate that Pax3/Pax7–induced myogenic progenitors remodel their molecular signature and functionally mature upon in vivo exposure to the adult muscle environment.

Tania Incitti, Alessandro Magli, Radbod Darabi, Ce Yuan, Karena Lin, Robert W. Arpke, Karim Azzag, Ami Yamamoto, Ron Stewart, James A. Thomson, Michael Kyba, and Rita C. R. Perlingeiro.

This work was made possible through the National Institutes of Health (NIH) grants R01 AR055299 (R.C.R.P.), AR071439 (R.C.R.P.) and AR055685 (M.K.), U01 HL100407R01 (R.C.R.P., M.K. 768 and J.A.T.), MDA351022 (M.K.), ADVault, Inc and MyDirectives.com (R.C.R.P.), and by Regenerative Medicine Minnesota (A.M.).

About the University of Minnesota Medical School
The University of Minnesota Medical School is at the forefront of learning and discovery, transforming medical care and educating the next generation of physicians. Our graduates and faculty produce high-impact biomedical research and advance the practice of medicine. Visit med.umn.edu to learn how the University of Minnesota is innovating all aspects of medicine.

The authors declare no competing financial interests.

About the Journal of Experimental Medicine The Journal of Experimental Medicine (JEM) features peer-reviewed research on immunology, cancer biology, stem cell biology, microbial pathogenesis, vascular biology, and neurobiology. All editorial decisions are made by research-active scientists in conjunction with in-house scientific editors. JEM makes all of its content free online no later than six months after publication. Established in 1896, JEM is published by Rockefeller University Press. For more information, visit jem.org.

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Feb 15, 2018   Fetal Timeline   Maternal Timeline   News  

Upon transplant, Pax3 & Pax7–induced myogenic muscle progenitor cells remodel
their molecular structure and mature when exposed to pre-existing adult muscle cells.

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