Metabolic Changes in Focal Brain Ischemia in Rats Treated With Human Induced Pluripotent Stem Cell-Derived Neural Precursors Confirm the Beneficial Effect of Transplanted Cells

Daniel Jirak; Natalia Ziolkowska; Karolina Turnovcova; Kristyna Karova; Eva Sykova; Pavla Jendelova; Nataliya Romanyuk

doi:10.3389/fneur.2019.01074

Metabolic Changes in Focal Brain Ischemia in Rats Treated With Human Induced Pluripotent Stem Cell-Derived Neural Precursors Confirm the Beneficial Effect of Transplanted Cells

Front Neurol. 2019 Oct 22:10:1074. doi: 10.3389/fneur.2019.01074. eCollection 2019.

Authors

Daniel Jirak^{1

2

3}, Natalia Ziolkowska^{1

2}, Karolina Turnovcova⁴, Kristyna Karova⁴, Eva Sykova⁵, Pavla Jendelova^{4

6}, Nataliya Romanyuk⁴

Affiliations

¹ MR Unit, Department of Diagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czechia.
² First Faculty of Medicine, Institute of Biophysics and Informatics, Charles University, Prague, Czechia.
³ Faculty of Health Studies, Technical University of Liberec, Liberec, Czechia.
⁴ Department of Neuroregeneration, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Czechia.
⁵ Department of Neuroscience, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Czechia.
⁶ Department of Neuroscience, Second Faculty of Medicine, Charles University, Prague, Czechia.

Abstract

There is currently no treatment for restoring lost neurological function after stroke. A growing number of studies have highlighted the potential of stem cells. However, the mechanisms underlying their beneficial effect have yet to be explored in sufficient detail. In this study, we transplanted human induced pluripotent stem cell-derived neural precursors (iPSC-NPs) in rat temporary middle cerebral artery occlusion (MCAO) model. Using magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) we monitored the effect of cells and assessed lesion volume and metabolite changes in the brain. We monitored concentration changes of myo-inositol (Ins), Taurine (Tau), Glycerophosphocholine+Phosphocholine (GPC+PCh), N-acetyl-aspartate+N-acetyl-aspartyl-glutamate (NAA+NAAG), Creatine+Phosphocreatine (Cr+PCr), and Glutamate+Glutamine (Glu+Gln) in the brains of control and iPSC-NP-transplanted rats. Based on initial lesion size, animals were divided into small lesion and big lesion groups. In the small lesion control group (SCL), lesion size after 4 months was three times smaller than initial measurements. In the small lesion iPSC-NP-treated group, lesion volume decreased after 1 month and then increased after 4 months. Although animals with small lesions significantly improved their motor skills after iPSC-NP transplantation, animals with big lesions showed no improvement. However, our MRI data demonstrate that in the big lesion iPSC-NP-treated (BTL) group, lesion size increased only up until 1 month after MCAO induction and then decreased. In contrast, in the big lesion control group, lesion size increased throughout the whole experiment. Significantly higher concentrations of Ins, Tau, GPC+PCh, NAA+NAAG, Cr+PCr, and Glu+Gln were found in in contralateral hemisphere in BTL animals 4 months after cell injection. Lesion volume decreased at this time point. Spectroscopic results of metabolite concentrations in lesion correlated with volumetric measurements of lesion, with the highest negative correlation observed for NAA+NAAG. Altogether, our results suggest that iPSC-NP transplantation decreases lesion volume and regulates metabolite concentrations within the normal range expected in healthy tissue. Further research into the ability of iPSC-NPs to differentiate into tissue-specific neurons and its effect on the long-term restoration of lesioned tissue is necessary.

Keywords: IMR; MRS; iPSC-NPs; magnetic resonance; metabolic changes; stroke.