Intrinsic Myogenic Potential of Skeletal Muscle-Derived Pericytes from Patients with Myotonic Dystrophy Type 1

Cornelia Rosanne Maria Ausems; Renée Henrica Lamberta Raaijmakers; Walterus Johannes Antonius Adriana van den Broek; Marieke Willemse; Baziel Gerardus Maria van Engelen; Derick Gert Wansink; Hans van Bokhoven

doi:10.1016/j.omtm.2019.09.002

Intrinsic Myogenic Potential of Skeletal Muscle-Derived Pericytes from Patients with Myotonic Dystrophy Type 1

Mol Ther Methods Clin Dev. 2019 Sep 12:15:120-132. doi: 10.1016/j.omtm.2019.09.002. eCollection 2019 Dec 13.

Authors

Cornelia Rosanne Maria Ausems^{1

2

3}, Renée Henrica Lamberta Raaijmakers^{1

2

3}, Walterus Johannes Antonius Adriana van den Broek³, Marieke Willemse³, Baziel Gerardus Maria van Engelen², Derick Gert Wansink³, Hans van Bokhoven¹

Affiliations

¹ Department of Human Genetics, Radboud University Medical Center, Donders lnstitute for Brain Cognition and Behavior, 6525 GA Nijmegen, the Netherlands.
² Department of Neurology, Radboud University Medical Center, Donders lnstitute for Brain Cognition and Behavior, 6500 HB Nijmegen, the Netherlands.
³ Department of Cell Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6525 GA Nijmegen, the Netherlands.

Abstract

Pericytes are multipotent, vessel-associated progenitors that exhibit high proliferative capacity, can cross the blood-muscle barrier, and have the ability to home to muscle tissue and contribute to myogenesis. Consequently, pericyte-based therapies hold great promise for muscular dystrophies. A complex multi-system disorder exhibiting muscular dystrophy for which pericytes might be a valuable cell source is myotonic dystrophy type 1 (DM1). DM1 is caused by an unstable (CTG)n repeat in the DMPK gene and characterized by skeletal muscle weakness, muscle wasting, and myotonia. We have successfully isolated alkaline phosphatase-positive pericytes from skeletal muscle of DM1 patients and a transgenic mouse model. Intranuclear (CUG)n RNA foci, a pathogenic DM1 hallmark, were identified in human and mouse pericytes. Notably, pericytes from DM1 patients maintained similar growth parameters and innate myogenic characteristics in vitro compared to cells from unaffected controls. Our in vitro results thus demonstrate the potential of pericytes to ameliorate muscle features in DM1 in a therapeutic setting.

Keywords: RNA toxicity; cell therapy; mesoangioblast; muscle stem cell; muscular dystrophy; myogenic progenitor cell; myotonic dystrophy; pericyte; triplet repeat expansion.