Theranostics 2019; 9(8):2395-2410. doi:10.7150/thno.29422
Donation of mitochondria by iPSC-derived mesenchymal stem cells protects retinal ganglion cells against mitochondrial complex I defect-induced degeneration
1. Department of Ophthalmology, The University of Hong Kong, Hong Kong SAR, P.R. China
2. Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, The Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China
3. Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P.R. China
4. Department of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China
5. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China
6. School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, P.R. China
7. Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
8. The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, P.R. China
9. GHM Institute of CNS Regeneration, Jinan University, Guangzhou, P.R. China
10. The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, P.R. China.
Rationale: Retinal ganglion cell (RGC) degeneration is extremely hard to repair or regenerate and is often coupled with mitochondrial dysfunction. Mesenchymal stem cells (MSCs)-based treatment has been demonstrated beneficial for RGC against degeneration. However, underlying mechanisms of MSC-provided RGC protection are largely unknown other than neuroprotective paracrine actions. In this study, we sought to investigate whether mitochondrial donation from induced pluripotent stem cell-derived MSC (iPSC-MSCs) could preserve RGC survival and restore retinal function.
Methods: iPSC-MSCs were injected into the vitreous cavity of one eye in NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) knockout (KO) and wild type mice. Phosphate buffer saline (PBS) or rotenone treated iPSC-MSCs were injected as control groups. Retinal function was detected by flash electroretinogram (ERG). Whole-mount immunofluorescence (IF), morphometric analysis, confocal microscopy imaging, polymerase chain reaction (PCR) of the retinas were conducted to investigate mitochondrial transfer from human iPSC-MSCs to mouse retina. Quantitative mouse cytokine arrays were carried out to measure retinal inflammatory response under difference treatments.
Results: RGC survival in the iPSC-MSC injected retina of Ndufs4 KO mice was significantly increased with improved retinal function. GFP labelled human mitochondria from iPSC-MSC were detected in the RGCs in the retina of Ndufs4 KO mice starting from 96 hours post injection. PCR result showed only human mitochondrial DNA without human nuclear DNA could be detected in the mouse retinas after iPSC-MSC treatment in Ndufs4 KO mice eye. Quantitative cytokine array analysis showed pro-inflammatory cytokines was also downregulated by this iPSC-MSC treatment.
Conclusion: Intravitreal transplanted iPSC-MSCs can effectively donate functional mitochondria to RGCs and protect against mitochondrial damage-induced RGC loss.
Keywords: mitochondrial defect, induced pluripotent stem cell derived-mesenchymal stem cell, mitochondrial transfer, retinal ganglion cell
Jiang D, Xiong G, Feng H, Zhang Z, Chen P, Yan B, Chen L, Gandhervin K, Ma C, Li C, Han S, Zhang Y, Liao C, Lee TL, Tse HF, Fu QL, Chiu K, Lian Q. Donation of mitochondria by iPSC-derived mesenchymal stem cells protects retinal ganglion cells against mitochondrial complex I defect-induced degeneration. Theranostics 2019; 9(8):2395-2410. doi:10.7150/thno.29422. Available from http://www.thno.org/v09p2395.htm