MS-Driven Metabolic Alterations Are Recapitulated in iPSC-Derived Astrocytes

Author(s):Show less -

Ghirotto, Bruno ; Oliveira, Danyllo F. ; Cipelli, Marcella ; Basso, Paulo J. ; Lima, Jean ; Breda, Cristiane N. S. ; Ribeiro, Henrique C. ; Silva, Camille C. C. ; Sertie, Andrea L. ; Oliveira, Antonio Edson R. ; Hiyane, Meire, I ; Caldini, Elia G. ; Sussulini, Alessandra ; Nakaya, Helder, I ; Kowaltowski, Alicia J. ; Oliveira, Enedina M. L. ; Zatz, Mayana ; Camara, Niels O. S.

• Document type: Journal article
• Source: ANNALS OF NEUROLOGY; v. 91, n. 5, p. 18-pg., 2022-03-17.

Abstract

Objective Astrocytes play a significant role in the pathology of multiple sclerosis (MS). Nevertheless, for ethical reasons, most studies in these cells were performed using the Experimental Autoimmune Encephalomyelitis model. As there are significant differences between human and mouse cells, we aimed here to better characterize astrocytes from patients with MS (PwMS), focusing mainly on mitochondrial function and cell metabolism. Methods We obtained and characterized induced pluripotent stem cell (iPSC)-derived astrocytes from three PwMS and three unaffected controls, and performed electron microscopy, flow cytometry, cytokine and glutamate measurements, gene expression, in situ respiration, and metabolomics. We validated our findings using a single-nuclei RNA sequencing dataset. Results We detected several differences in MS astrocytes including: (i) enrichment of genes associated with neurodegeneration, (ii) increased mitochondrial fission, (iii) increased production of superoxide and MS-related proinflammatory chemokines, (iv) impaired uptake and enhanced release of glutamate, (v) increased electron transport capacity and proton leak, in line with the increased oxidative stress, and (vi) a distinct metabolic profile, with a deficiency in amino acid catabolism and increased sphingolipid metabolism, which have already been linked to MS. Interpretation Here we describe the metabolic profile of iPSC-derived astrocytes from PwMS and validate this model as a very powerful tool to study disease mechanisms and to perform non-invasive drug targeting assays in vitro. Our findings recapitulate several disease features described in patients and provide new mechanistic insights into the metabolic rewiring of astrocytes in MS, which could be targeted in future therapeutic studies. ANN NEUROL 2022 (AU)

• FAPESP's process: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/23460-0 - Evaluation of the mitochondrial dynamics in astrocytes and its impact on the inflammatory response in experimental autoimmune encephalomyelitis
• Grantee: Bruno Ghirotto Nunes
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 20/06970-5 - Mitochondrial ion transporters as sensors and regulators in energy metabolism
• Grantee: Alicia Juliana Kowaltowski
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC