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

Regulation of mitochondrial functions impacts on neuronaldifferentiation and maturation. Studying these processes is of bothfundamental and practical importance for regenerative neurobiology.This work was aimed to characterize the changes in mitochondrialfission and their link with the activation of oxidative phosphorylation(metabolic switch) during the maturation of human induced pluripotentstem cell (iPSC)-derived neural progenitors xenografted in the ratstriatum. Wistar rats (n =15) were unilaterally injected into the caudate nucleus with neuralprecursors derived from the human iPSCs. Changes in the localizationand expression of neuronal differentiation markers, such as nestin,NeuN, neuron-specific enolase, mitochondrial outer membrane protein,ATP synthase, and mitochondrial fission protein Drp1, were assessedby immunostaining. Measurements of grafted cells were performed2 weeks, 3 and 6 months after surgery. The maturation of graftedneurons was associated with fluctuations in morphometric parametersof the mitochondrial fraction and Drp1 levels. An increase in mitochondrialfission was detected 3 months after grafting, preceded by an increasein ATP synthase level by month 6 and switching grafted neurons tooxidative phosphorylation. The experiment revealed a link betweenmitochondrial dynamics and changes in the metabolic profile andmaturation of grafted neurons. The regulation of mitochondrial dynamicsmay have future implications for developing methods to improve theintegration of grafted neurons into recipient brain structures.