Intra-arterial transplantation of stem cells in large animals as a minimally-invasive strategy for the treatment of disseminated neurodegeneration

Izabela Malysz-Cymborska,Piotr Walczak,Lukasz Kalkowski,Dominika Golubczyk,Miroslaw Janowski,Michal Zawadzki,Joanna Kwiatkowska,Joanna Głodek,Piotr Holak,Zbigniew Adamiak,Kamila Milewska,Joanna Sanford

doi:10.1038/s41598-021-85820-3

Abstract

Stem cell transplantation proved promising in animal models of neurological diseases; however, in conditions with disseminated pathology such as ALS, delivery of cells and their broad distribution is challenging. To address this problem, we explored intra-arterial (IA) delivery route, of stem cells. The goal of this study was to investigate the feasibility and safety of MRI-guided transplantation of glial restricted precursors (GRPs) and mesenchymal stem cells (MSCs) in dogs suffering from ALS-like disease, degenerative myelopathy (DM). Canine GRP transplantation in dogs resulted in rather poor retention in the brain, so MSCs were used in subsequent experiments. To evaluate the safety of MSC intraarterial transplantation, naïve pigs (n = 3) were used as a pre-treatment control before transplantation in dogs. Cells were labeled with iron oxide nanoparticles. For IA transplantation a 1.2-French microcatheter was advanced into the middle cerebral artery under roadmap guidance. Then, the cells were transplanted under real-time MRI with the acquisition of dynamic T2*-weighted images. The procedure in pigs has proven to be safe and histopathology has demonstrated the successful and predictable placement of transplanted porcine MSCs. Transplantation of canine MSCs in DM dogs resulted in their accumulation in the brain. Interventional and follow-up MRI proved the procedure was feasible and safe. Analysis of gene expression after transplantation revealed a reduction of inflammatory factors, which may indicate a promising therapeutic strategy in the treatment of neurodegenerative diseases.

Highlights

Stem cell transplantation proved promising in animal models of neurological diseases; in conditions with disseminated pathology such as amyotrophic lateral sclerosis (ALS), delivery of cells and their broad distribution is challenging
Trans-catheter perfusion territory was visualized using the IA injection of Feraheme contrast (AMAG pharmaceuticals, Waltham, USA) and the infusion rate was adjusted to achieve adequate coverage throughout the ipsilateral hemisphere. canine GRPs (cGRPs) were injected IA while acquiring dynamic GE-EPI scans using the infusion speed that was predetermined by contrast agent pre-injection
During cGRP infusion, signal intensity change was observed in the ipsilateral cortex, indicating labeled cells entered cortical circulation (Fig. 1A)

Summary

Introduction

Stem cell transplantation proved promising in animal models of neurological diseases; in conditions with disseminated pathology such as ALS, delivery of cells and their broad distribution is challenging. To address this problem, we explored intra-arterial (IA) delivery route, of stem cells. The goal of this study was to investigate the feasibility and safety of MRI-guided transplantation of glial restricted precursors (GRPs) and mesenchymal stem cells (MSCs) in dogs suffering from ALSlike disease, degenerative myelopathy (DM). The size and the cerebral vasculature of the dog brain enables navigation of IA catheters towards distal cerebral vessels and targeted delivery of stem cells under the guidance of clinical imaging equipment, further improving clinical relevance. Given the above and the etiology of DM, we believe that the evaluation of the therapeutic potential of both GRPs and MSCs after their targeted intra-arterial administration to the brain is warranted

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