Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich's ataxia.

Abstract

Friedreich's ataxia (FRDA) is an incurable autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the FXN gene. We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart. Transplanted HSPCs engrafted and then differentiated into microglia in the brain and spinal cord and into macrophages in the DRGs, heart, and muscle of YG8R FRDA mice. We observed the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to FRDA mouse neurons and muscle myocytes in vivo. Our results show the HSPC-mediated phenotypic rescue of FRDA in YG8R mice and suggest that this approach should be investigated further as a strategy for treating FRDA.

• Authors: Celine J Rocca, Spencer M Goodman, Jennifer N Dulin, Joseph H Haquang, Ilya Gertsman, Jordan Blondelle, Janell L M Smith, Charles J Heyser, Stephanie Cherqui
• Journal: Science translational medicine (Sci Transl Med) Vol. 9 Issue 413 (Oct 25 2017) ISSN: 1946-6242 [Electronic] United States
• PMID: 29070698 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Iron-Binding Proteins
• Mitochondrial Proteins
• frataxin

Topics

• Animals
• Behavior, Animal
• Cell Differentiation
• Disease Models, Animal
• Fibroblasts (metabolism)
• Friedreich Ataxia (pathology, physiopathology, therapy)
• Hematopoietic Stem Cell Transplantation
• Hematopoietic Stem Cells (cytology, metabolism)
• Iron-Binding Proteins (metabolism)
• Locomotion
• Macrophages (metabolism)
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia (metabolism)
• Mitochondria (metabolism)
• Mitochondrial Proteins (metabolism)
• Nervous System (pathology)
• Phagocytosis
• Sensory Receptor Cells (pathology)