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Human satellite cells have regenerative capacity and are genetically manipulable
Andreas Marg, … , Zsuzsanna Izsvák, Simone Spuler
Andreas Marg, … , Zsuzsanna Izsvák, Simone Spuler
Published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4257-4265. https://doi.org/10.1172/JCI63992.
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Technical Advance Genetics Muscle biology

Human satellite cells have regenerative capacity and are genetically manipulable

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Abstract

Muscle satellite cells promote regeneration and could potentially improve gene delivery for treating muscular dystrophies. Human satellite cells are scarce; therefore, clinical investigation has been limited. We obtained muscle fiber fragments from skeletal muscle biopsy specimens from adult donors aged 20 to 80 years. Fiber fragments were manually dissected, cultured, and evaluated for expression of myogenesis regulator PAX7. PAX7+ satellite cells were activated and proliferated efficiently in culture. Independent of donor age, as few as 2 to 4 PAX7+ satellite cells gave rise to several thousand myoblasts. Transplantation of human muscle fiber fragments into irradiated muscle of immunodeficient mice resulted in robust engraftment, muscle regeneration, and proper homing of human PAX7+ satellite cells to the stem cell niche. Further, we determined that subjecting the human muscle fiber fragments to hypothermic treatment successfully enriches the cultures for PAX7+ cells and improves the efficacy of the transplantation and muscle regeneration. Finally, we successfully altered gene expression in cultured human PAX7+ satellite cells with Sleeping Beauty transposon–mediated nonviral gene transfer, highlighting the potential of this system for use in gene therapy. Together, these results demonstrate the ability to culture and manipulate a rare population of human tissue-specific stem cells and suggest that these PAX7+ satellite cells have potential to restore gene function in muscular dystrophies.

Authors

Andreas Marg, Helena Escobar, Sina Gloy, Markus Kufeld, Joseph Zacher, Andreas Spuler, Carmen Birchmeier, Zsuzsanna Izsvák, Simone Spuler

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Figure 4

Transplantation of HMFFs into NOG mice.

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            Transplantation of HMFFs into NOG mice.
          
Anterior...
Anterior tibial muscles of NOG mice were transplanted with 4 to 8 HMFFs. Human cells were detected with anti-human lamin A/C antibody (yellow). Transplantation of HMFFs without prior irradiation resulted in human cells located interstitially in the host tissue (group A, Table 1). Three weeks after irradiation with 18 Gy and transplantation of HMFFs, fusing human myotubes were identified (group B). Seven weeks after transplantation, human myofibers had formed (group C). HMFFs transplanted after hypothermic treatment (ht) resulted in large human myofibers that contained multiple human nuclei (group D). Scale bar: 200 μm (top row); 50 μm (bottom row, first, third, and fourth images); 20 μm (bottom row, second image).

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