Intra-Arterial Stem Cell Transplantation in Experimental Stroke in Rats: Real-Time MR Visualization of Transplanted Cells Starting With Their First Pass Through the Brain With Regard to the Therapeutic Action

Daria D Namestnikova; Ilya L Gubskiy; Veronica A Revkova; Kirill K Sukhinich; Pavel A Melnikov; Anna N Gabashvili; Elvira A Cherkashova; Daniil A Vishnevskiy; Victoria V Kurilo; Veronica V Burunova; Alevtina S Semkina; Maxim A Abakumov; Leonid V Gubsky; Vladimir P Chekhonin; Jan-Eric Ahlfors; Vladimir P Baklaushev; Konstantin N Yarygin

doi:10.3389/fnins.2021.641970

Intra-Arterial Stem Cell Transplantation in Experimental Stroke in Rats: Real-Time MR Visualization of Transplanted Cells Starting With Their First Pass Through the Brain With Regard to the Therapeutic Action

Front Neurosci. 2021 Mar 2:15:641970. doi: 10.3389/fnins.2021.641970. eCollection 2021.

Authors

Daria D Namestnikova^{1

2}, Ilya L Gubskiy^{1

2}, Veronica A Revkova³, Kirill K Sukhinich⁴, Pavel A Melnikov^{3

5}, Anna N Gabashvili⁶, Elvira A Cherkashova^{1

2}, Daniil A Vishnevskiy¹, Victoria V Kurilo¹, Veronica V Burunova⁷, Alevtina S Semkina^{1

6}, Maxim A Abakumov^{1

6}, Leonid V Gubsky^{1

2}, Vladimir P Chekhonin^{1

5}, Jan-Eric Ahlfors⁸, Vladimir P Baklaushev³, Konstantin N Yarygin^{7

9}

Affiliations

¹ Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University of the Ministry of Healthcare of Russian Federation, Moscow, Russia.
² Radiology and Clinical Physiology Scientific Research Center, Federal Center of Brain Research and Neurotechnologies of the Federal Medical Biological Agency of Russian Federation, Moscow, Russia.
³ Cell Technology Laboratory, Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies of the Federal Medical Biological Agency of Russian Federation, Moscow, Russia.
⁴ Laboratory of Problems of Regeneration, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow, Russia.
⁵ Department of Fundamental and Applied Neurobiology, Serbsky Federal Medical Research Centre of Psychiatry and Narcology of the Ministry of Healthcare of Russian Federation, Moscow, Russia.
⁶ Laboratory of Biomedical Nanomaterials, National University of Science and Technology "MISIS", Moscow, Russia.
⁷ Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry of the Russian Academy of Sciences, Moscow, Russia.
⁸ New World Laboratories, Laval, QC, Canada.
⁹ Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare of the Russian Federation, Moscow, Russia.

Abstract

Cell therapy is an emerging approach to stroke treatment with a potential to limit brain damage and enhance its restoration after the acute phase of the disease. In this study we tested directly reprogrammed neural precursor cells (drNPC) derived from adult human bone marrow cells in the rat middle cerebral artery occlusion (MCAO) model of acute ischemic stroke using human placenta mesenchymal stem cells (pMSC) as a positive control with previously confirmed efficacy. Cells were infused into the ipsilateral (right) internal carotid artery of male Wistar rats 24 h after MCAO. The main goal of this work was to evaluate real-time distribution and subsequent homing of transplanted cells in the brain. This was achieved by performing intra-arterial infusion directly inside the MRI scanner and allowed transplanted cells tracing starting from their first pass through the brain vessels. Immediately after transplantation, cells were observed in the periphery of the infarct zone and in the brain stem, 15 min later small numbers of cells could be discovered deep in the infarct core and in the contralateral hemisphere, where drNPC were seen earlier and in greater numbers than pMSC. Transplanted cells in both groups could no longer be detected in the rat brain 48-72 h after infusion. Histological and histochemical analysis demonstrated that both the drNPC and pMSC were localized inside blood vessels in close contact with the vascular wall. No passage of labeled cells through the blood brain barrier was observed. Additionally, the therapeutic effects of drNPC and pMSC were compared. Both drNPC and pMSC induced substantial attenuation of neurological deficits evaluated at the 7th and 14th day after transplantation using the modified neurological severity score (mNSS). Some of the effects of drNPC and pMSC, such as the influence on the infarct volume and the survival rate of animals, differed. The results suggest a paracrine mechanism of the positive therapeutic effects of IA drNPC and pMSC infusion, potentially enhanced by the cell-cell interactions. Our data also indicate that the long-term homing of transplanted cells in the brain is not necessary for the brain's functional recovery.

Keywords: cell reprogramming; directly reprogrammed neural precursor cells; experimental stroke; intra-arterial cell transplantation; mesenchymal stem cells; middle cerebral artery occlusion; real-time MRI.