Placenta-derived mesenchymal stromal cells and their exosomes exert therapeutic effects in Duchenne muscular dystrophy.

Abstract

Duchenne muscular dystrophy (DMD) is a degenerative lethal, X-linked disease of skeletal and cardiac muscles caused by mutations in the dystrophin gene. Cell therapy using different cell types, including mesenchymal stromal cells (MSCs), has been considered as a potential approach for the treatment of DMD. MSCs can be obtained from autologous sources such as bone marrow and adipose tissues or from allogeneic placenta and umbilical cord. The safety and therapeutic impact of these cells has been demonstrated in pre-clinical and clinical studies and their functions are attributed to paracrine effects that are mediated by secreted cytokines and extracellular vesicles. Here, we studied the therapeutic effects of placenta-derived MSCs (PL-MSCs) and their secreted exosomes using mouse and human myoblasts from healthy controls, Duchenne patients and mdx mice. Treatment of myoblasts with conditioned medium or exosomes secreted by PL-MSCs increased the differentiation of these cells and decreased the expression of fibrogenic genes in DMD patient myoblasts. In addition, these treatments also increased the expression of utrophin in these cells. Using a quantitative miR-29c reporter, we demonstrated that the PL-MSC effects were partly mediated by the transfer of exosomal miR-29c. Intramuscular transplantation of PL-MSCs in mdx mice resulted in decreased creatine kinase levels. PL-MSCs significantly decreased the expression of TGF-β and the level of fibrosis in the diaphragm and cardiac muscles, inhibited inflammation and increased utrophin expression. In vivo imaging analyses using MSCs labeled with gold nanoparticles or fluorescent dyes demonstrated localization of the cells in the muscle tissues up to 3 weeks post treatment. Altogether, these results demonstrate that PL-MSCs and their secreted exosomes have important clinical applications in cell therapy of DMD partly via the targeted delivery of exosomal miR-29c.

• Authors: Ariel Bier, Peter Berenstein, Noam Kronfeld, Daria Morgoulis, Amotz Ziv-Av, Hodaya Goldstein, Gila Kazimirsky, Simona Cazacu, Rinat Meir, Rachela Popovtzer, Amir Dori, Chaya Brodie
• Journal: Biomaterials (Biomaterials) Vol. 174 Pg. 67-78 (08 2018) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 29783118 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018. Published by Elsevier Ltd.

Chemical References

• Culture Media, Conditioned
• Dystrophin
• Fluorescent Dyes
• MicroRNAs
• Transforming Growth Factor beta
• Utrophin
• Gold

Topics

• Adipose Tissue (metabolism)
• Animals
• Cell Differentiation (drug effects)
• Culture Media, Conditioned (metabolism)
• Dystrophin (metabolism)
• Exosomes (metabolism)
• Extracellular Vesicles (metabolism)
• Female
• Fluorescent Dyes (chemistry)
• Gene Expression Regulation (drug effects)
• Gold (chemistry)
• Humans
• Mesenchymal Stem Cell Transplantation (methods)
• Mesenchymal Stem Cells (metabolism)
• Metal Nanoparticles (chemistry)
• Mice, Inbred mdx
• MicroRNAs (metabolism)
• Muscular Dystrophy, Duchenne (drug therapy)
• Myoblasts (drug effects)
• Placenta (cytology, drug effects)
• Pregnancy
• Transfection (methods)
• Transforming Growth Factor beta (metabolism)
• Umbilical Cord (metabolism)
• Utrophin (metabolism)