Transplantation of PSC-derived myogenic progenitors counteracts disease phenotypes in FSHD mice

Karim Azzag; Darko Bosnakovski; Sudheer Tungtur; Peter Salama; Michael Kyba; Rita C.R. Perlingeiro

doi:10.1038/s41536-022-00249-0

Transplantation of PSC-derived myogenic progenitors counteracts disease phenotypes in FSHD mice

Karim Azzag, Darko Bosnakovski, Sudheer Tungtur, Peter Salama, Michael Kyba, Rita C.R. Perlingeiro

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Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive myopathy caused by improper silencing of the DUX4 gene, leading to fibrosis, muscle atrophy, and fatty replacement. Approaches focused on muscle regeneration through the delivery of stem cells represent an attractive therapeutic option for muscular dystrophies. To investigate the potential for cell transplantation in FSHD, we have used the doxycycline-regulated iDUX4pA-HSA mouse model in which low-level DUX4 can be induced in skeletal muscle. We find that mouse pluripotent stem cell (PSC)-derived myogenic progenitors engraft in muscle actively undergoing DUX4-mediated degeneration. Donor-derived muscle tissue displayed reduced fibrosis and importantly, engrafted muscles showed improved contractile specific force compared to non-transplanted controls. These data demonstrate the feasibility of replacement of diseased muscle with PSC-derived myogenic progenitors in a mouse model for FSHD, and highlight the potential for the clinical benefit of such a cell therapy approach.

Original language	English (US)
Article number	43
Journal	npj Regenerative Medicine
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41536-022-00249-0
State	Published - Dec 2022

Bibliographical note

Funding Information:
This project was supported by funds from the FSHD Society (FSHS-22018-01), the Dr. Bob and Jean Smith Foundation, and NIH-NIAMS, grants R01 AR071439 and AR078571 (R.C.R.P.) and AR055685 (M.K.). D.B. was partly supported by the Friends of FSH Research. We thank Robert Grange (Virginia Tech) and Radbod Darabi (UT Health Science Center) for guidance with the in situ force measurements, Mark Sanders and Yung Kim (University of Minnesota) for assistance with the confocal imaging, Bryce Binstadt (University of Minnesota) for the mTmG mice, and Cynthia Faraday for graphical design. The monoclonal antibody to MHC was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa.

Funding Information:
This project was supported by funds from the FSHD Society (FSHS-22018-01), the Dr. Bob and Jean Smith Foundation, and NIH-NIAMS, grants R01 AR071439 and AR078571 (R.C.R.P.) and AR055685 (M.K.). D.B. was partly supported by the Friends of FSH Research. We thank Robert Grange (Virginia Tech) and Radbod Darabi (UT Health Science Center) for guidance with the in situ force measurements, Mark Sanders and Yung Kim (University of Minnesota) for assistance with the confocal imaging, Bryce Binstadt (University of Minnesota) for the mTmG mice, and Cynthia Faraday for graphical design. The monoclonal antibody to MHC was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa.

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© 2022, The Author(s).

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title = "Transplantation of PSC-derived myogenic progenitors counteracts disease phenotypes in FSHD mice",

abstract = "Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive myopathy caused by improper silencing of the DUX4 gene, leading to fibrosis, muscle atrophy, and fatty replacement. Approaches focused on muscle regeneration through the delivery of stem cells represent an attractive therapeutic option for muscular dystrophies. To investigate the potential for cell transplantation in FSHD, we have used the doxycycline-regulated iDUX4pA-HSA mouse model in which low-level DUX4 can be induced in skeletal muscle. We find that mouse pluripotent stem cell (PSC)-derived myogenic progenitors engraft in muscle actively undergoing DUX4-mediated degeneration. Donor-derived muscle tissue displayed reduced fibrosis and importantly, engrafted muscles showed improved contractile specific force compared to non-transplanted controls. These data demonstrate the feasibility of replacement of diseased muscle with PSC-derived myogenic progenitors in a mouse model for FSHD, and highlight the potential for the clinical benefit of such a cell therapy approach.",

author = "Karim Azzag and Darko Bosnakovski and Sudheer Tungtur and Peter Salama and Michael Kyba and Perlingeiro, {Rita C.R.}",

note = "Funding Information: This project was supported by funds from the FSHD Society (FSHS-22018-01), the Dr. Bob and Jean Smith Foundation, and NIH-NIAMS, grants R01 AR071439 and AR078571 (R.C.R.P.) and AR055685 (M.K.). D.B. was partly supported by the Friends of FSH Research. We thank Robert Grange (Virginia Tech) and Radbod Darabi (UT Health Science Center) for guidance with the in situ force measurements, Mark Sanders and Yung Kim (University of Minnesota) for assistance with the confocal imaging, Bryce Binstadt (University of Minnesota) for the mTmG mice, and Cynthia Faraday for graphical design. The monoclonal antibody to MHC was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa. Funding Information: This project was supported by funds from the FSHD Society (FSHS-22018-01), the Dr. Bob and Jean Smith Foundation, and NIH-NIAMS, grants R01 AR071439 and AR078571 (R.C.R.P.) and AR055685 (M.K.). D.B. was partly supported by the Friends of FSH Research. We thank Robert Grange (Virginia Tech) and Radbod Darabi (UT Health Science Center) for guidance with the in situ force measurements, Mark Sanders and Yung Kim (University of Minnesota) for assistance with the confocal imaging, Bryce Binstadt (University of Minnesota) for the mTmG mice, and Cynthia Faraday for graphical design. The monoclonal antibody to MHC was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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Transplantation of PSC-derived myogenic progenitors counteracts disease phenotypes in FSHD mice

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