Mitochondrial Dynamics and Metabolic Remodeling in a Xenograft of Human iPSC-Derived Neural Precursors

Abstract

Regulation of mitochondrial functions impacts on neuronal differentiation and maturation. Studying these processes is of both fundamental and practical importance for regenerative neurobiology. This work was aimed to characterize the changes in mitochondrial fission and their link with the activation of oxidative phosphorylation (metabolic switch) during the maturation of human induced pluripotent stem cell (iPSC)-derived neural progenitors xenografted in the rat striatum. Wistar rats (n = 15) were unilaterally injected into the caudate nucleus with neural precursors derived from the human iPSCs. Changes in the localization and expression of neuronal differentiation markers, such as nestin, NeuN, neuron-specific enolase, mitochondrial outer membrane protein, ATP synthase, and mitochondrial fission protein Drp1, were assessed by immunostaining. Measurements of grafted cells were performed 2 weeks, 3 and 6 months after surgery. The maturation of grafted neurons was associated with fluctuations in morphometric parameters of the mitochondrial fraction and Drp1 levels. An increase in mitochondrial fission was detected 3 months after grafting, preceded by an increase in ATP synthase level by month 6 and switching grafted neurons to oxidative phosphorylation. The experiment revealed a link between mitochondrial dynamics and changes in the metabolic profile and maturation of grafted neurons. The regulation of mitochondrial dynamics may have future implications for developing methods to improve the integration of grafted neurons into recipient brain structures.