Aorta-derived mesoangioblasts for cell therapy of cardiomyopathy in Duchenne Muscular Dystrophy

ABSTRACT Aorta-derived mesoangioblasts (ADM) are multipotent adult stem cells that differentiate to adipocytes, smooth muscle cells, skeletal myotubes, oligodendrocyte precursors, and cardiomyocytes, indicating that they can be used for regeneration in severe disease in which multiple tissues are affected. Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease, and patients with DMD do not survive beyond their early 30s. The most common causes of the death in DMD patients are cardiac and respiratory failure. Currently, there are advanced treatments and equipment for improving respiratory function so that it is possible to prolong the life of DMD patients. With increased lifespan dilated cardiomyopathy (DCM) has become prevalent in patients with DMD, and all patients develop DCM by 18 years of age about their mid-teen. However there have been not many studies that have focused on therapy for cardiomyopathy in DMD. This project is focused on determining whether ADM ameliorate cardiomyopathy in murine models for DMD, mdx and mdx/utrn-/- mice, and whether ADM are good candidates for cell-based therapy of DCM in DMD. In the first part of study, mdx/utrn-/- mice were characterized to determine whether they develop DCM similar to patients with DMD as a good disease model of DMD. DCM was not observed in mdx/utrn-/- mice at 5 weeks of age. However cardiac function and ventricular wall thickness decreased continuously at 10 and 15 weeks of age and an increase in fibrosis in the left ventricular posterior wall was observed, similar to patients with DMD. In the second part of the study we examined whether ADM differentiate into cardiomyocytes to determine whether they were a good source for stem cell therapy in DMD. ADM differentiated to cardiomyocytes that expressed of cardiac specific mRNAs and proteins in vitro and in vivo, and restored dystrophin in the heart of young mdx mice after intramyocardiac injection. In the last study ADM were transplanted into hearts of mdx and mdx/utrn-/- mice and the effect of ADM transplantation on DCM was examined. With ADM transplantation mdx/utrn-/- mice did not develop DCM in contrast to sham-injected mice which exhibited decreased heart function. Increased angiogenesis and proliferation were detected in mdx/utrn-/- heart after ADM transplantation which may contribute to the positive effects of ADM in mdx/utrn-/- cardiac muscle. In addition restored dystrophin was detected in mdx/utrn-/- heart after ADM injection. However, no cardiac functional improvement or dystrophin protein was detected in mdx mice with ADM transplantation. To conclude development of DCM in mdx/utrn-/- mice was prevented or delayed by ADM transplantation correlating with angiogenesis and increased cell proliferation as well as restored dystrophin expression. ADM may therefore be a good stem cell source for treatment of DCM in DMD by preventing or delaying their development. However ADM are not a good stem cell source for treatment of pre-existing DCM at late disease stages.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Animal Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2012

Author dc:creator

• Chun, Ju Lan

Contributors dc:contributor

• Berry-Miller, Suzanne E.
• Bahr, Janice M.
• Wheeler, Matthew B.
• Miller, David J.
• O'Brien, Robert T.
• Hofmann, Marie-Claude

• Aorta-derived mesoangioblasts
• stem cell therapy
• dilated cardiomyopathy
• Duchenne Muscular Dystrophy

Statement dc:rights

• Copyright 2012 Ju Lan Chun

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/31980

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/31980