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.
Highlights
Stroke is a neurodegenerative disorder and the leading cause of disability in adult humans
Two existing groups were divided as follows: small control lesions without transplantation (SCL; n = 6), small lesions treated with iPSC-NPs (STL; n = 10), big control lesions without transplantation (BCL; n = 6), and big lesions treated with iPSC-NPs (BTL; n = 10)
We confirm the beneficial effect of induced pluripotent stem cell-derived neural precursors on post-ischemic tissue repair in animals with small lesions as well as in those with big lesions
Summary
Stroke is a neurodegenerative disorder and the leading cause of disability in adult humans. A growing number of studies have highlighted the potential of stem cell transplantation and more differentiated neural cell transplantation as intriguing therapeutic approaches to post-stroke reparation. It has been shown that transplantation of human iPSC-derived cells is a safe and efficient approach to promoting recovery after stroke, supplying the injured brain with new neurons for replacement [6]. Grafted human iPSCs-NPs have been shown to survive, differentiate into neurons and ameliorate functional deficits in stroke-injured neonatal [11], and aged brains [7]. Their strong therapeutic potential has been demonstrated in large animal models [9]. The mechanisms of iPSC-NPs in stroke treatment have yet to be investigated in sufficient detail
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