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

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.

Highlights

In a search for myogenic cells from non-somite origin, De Angelis and colleagues were the first to show that vessel-associated cells isolated from the wall of the embryonic dorsal aorta, generally called mesoangioblasts, hold myogenic potential.[1,2] Follow-up research revealed that their postnatal analogs surrounding vessels in postnatal tissues, pericytes, have the capacity to contribute to myogenesis.[3]
Encouraging results in the field of Duchenne muscular dystrophy (DMD),[8] limb-girdle muscular dystrophy (LGMD),[9] and facioscapulohumeral muscular dystrophy (FSHD)[10] made us wonder whether functional pericytes are present in postnatal tissues of patients with the variable and most prevalent neuromuscular disease, myotonic dystrophy type 1 (DM1)
Our results indicate that pericytes from skeletal muscle of DM1 patients and DMSXL mice may pave the road for cell therapy approaches

Summary

INTRODUCTION

In a search for myogenic cells from non-somite origin, De Angelis and colleagues were the first to show that vessel-associated cells isolated from the wall of the embryonic dorsal aorta, generally called mesoangioblasts, hold myogenic potential.[1,2] Follow-up research revealed that their postnatal analogs surrounding vessels in postnatal tissues, pericytes, have the capacity to contribute to myogenesis.[3]. According to the RNA dominance theory, expression of DMPK RNA with abnormal repeat length may affect proper muscle development and have consequences for regenerative muscle capacity in adulthood.[34] Both the timing and the level of expression of pathogenic repeats will influence the type and the extent of down-stream toxicity caused by for example RNP binding or RAN translation products.[17,35] Pericytes isolated from HET and HOM DMSXL mice displayed expanded DMPK transcripts in the form of fluorescent in situ hybridization (FISH)-detectable RNP complexes in the nucleus, generally termed foci, after hybridization with a CAG repeat probe. Under the conditions tested in this study, none of the four parameters showed a significant difference between control and patient pericyte populations, and we conclude that DM1 pericytes still maintain normal, intrinsic myogenic capacity, independent of the disease state

DISCUSSION

Findings

MATERIALS AND METHODS