Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment.

Pablo Bonilla,Michael Edel,Xavier Navarro,Xavier Navarro,Joaquim Hernandez,Miguel A González-Pérez,Hoda Elkhenany,Hoda Elkhenany,Esther Giraldo,Victoria Moreno-Manzano,Ana Alastrue-Agudo,Esther Giraldo,María J Vicent

doi:10.3390/ijms22115966

Abstract

We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of β-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.

Highlights

The physiopathology of spinal cord injury (SCI) involves the disruption of spinal pathways and a primary succession of processes initiated immediately after trauma that prompt rapid and massive cell death within the nervous tissue and the concomitant invasion of ectopic immune and fibrotic cells [1]
We report on the development of an enhanced synergistic combination therapy comprising polyacetal–curcumin nanoconjugate (PA-C) and induced pluripotent stem cells (iPSC)-neural stem cells (NSC) + mesenchymal stem cells (MSC) treatment as a treatment option for severe sub-acute traumatic SCI
We evaluated the functional relevance of induced neurite elongation by PA-C treatment in an inhibitory environment by treating iPSC-NSC with lysophosphatidic acid (LPA), which activates the Rho/ROCK pathway and induces growth cone retraction and neurite collapse [41,42]

Summary

Introduction

The physiopathology of spinal cord injury (SCI) involves the disruption of spinal pathways and a primary succession of processes initiated immediately after trauma that prompt rapid and massive cell death within the nervous tissue and the concomitant invasion of ectopic immune and fibrotic cells [1]. The use of neural stem cells (NSC) [4], represents a potentially effective treatment approach for SCI. The US Food and Drug Administration (FDA) approved an immortalized NSC line (NSI-566), derived from human early fetal spinal cord tissue, to treat chronic SCI in phase I clinical trials reporting no serious adverse effects [9]. The administration of NSI-566 in several pre-clinical models of SCI (rodents [10] and non-human primates [11]) prompted significant improvements to neurological function and suppressed spasticity by supporting extensive axonal sprouting and the development of synaptic contacts with host neurons. NSI-566 transplantation requires immunosuppression, which is a disadvantage that could be avoided via the use of derivatives of autologous or immune-compatible induced pluripotent stem cells (iPSC)

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