Multiple intracerebroventricular injections of human umbilical cord mesenchymal stem cells delay motor neurons loss but not disease progression of SOD1G93A mice

Abstract

Stem cell therapy is considered a promising approach in the treatment of amyotrophic lateral sclerosis (ALS) and mesenchymal stem cells (MSCs) seem to be the most effective in ALS animal models. The umbilical cord (UC) is a source of highly proliferating fetal MSCs, more easily collectable than other MSCs. Recently we demonstrated that human (h) UC-MSCs, double labeled with fluorescent nanoparticles and Hoechst-33258 and transplanted intracerebroventricularly (ICV) into SOD1G93A transgenic mice, partially migrated into the spinal cord after a single injection. This prompted us to assess the effect of repeated ICV injections of hUC-MSCs on disease progression in SOD1G93A mice. Although no transplanted cells migrated to the spinal cord, a partial but significant protection of motor neurons (MNs) was found in the lumbar spinal cord of hUC-MSCs-treated SOD1G93A mice, accompanied by a shift from a pro-inflammatory (IL-6, IL-1β) to anti-inflammatory (IL-4, IL-10) and neuroprotective (IGF-1) environment in the lumbar spinal cord, probably linked to the activation of p-Akt survival pathway in both motor neurons and reactive astrocytes. However, this treatment neither prevented the muscle denervation nor delayed the disease progression of mice, emphasizing the growing evidence that protecting the motor neuron perikarya is not sufficient to delay the ALS progression.

RETRACTED ARTICLE: Human Umbilical Cord Mesenchymal Stem Cells-Derived Exosomal MicroRNA-18b-3p Inhibits the Occurrence of Preeclampsia by Targeting LEP

“…Human umbilical cord (huc) is a suitable source of mesenchymal stem cells (MSCs) which secrete a variety of trophic factors and cytokines as well as show strong anti-inflammatory and immunomodulatory capacities [6]. A study has verified that PE accelerates neuroglial marker expression in umbilical cord Wharton's jelly-derived MSCs [7].…”

Mesenchymal Stem Cells: A Potential Therapeutic Approach for Amyotrophic Lateral Sclerosis?

“…The beneficial effects may be mediated by the activation of the p-Akt survival pathway in motor neurons and astrocytes. However, UC-MSC administration did not prevent muscle denervation and disease progression in SOD1 G93A mice [57].…”

Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy

“…Indeed, NSCs can also elicit protection or regeneration of perilesional tissues and circuitries [31,33]. In the past ten years, several preclinical studies focusing on the use of stem cells in ALS transgenic animal models have shown promising results [26,27,31,[34][35][36][37]. Furthermore, Teng and colleagues demonstrated an increased therapeutic effect when performing multiple dose-escalating injections in different CNS sites, indicating the importance of administering enough cells into critically functional areas to hinder ALS-induced damage [31].…”

“…Currently, despite extensive research efforts, no successful treatment for MNDs is available. Nonetheless, preclinical studies on stem cell-based transplantation therapy have yielded significant and interesting results, showing neuroprotective effects, improved functional outcomes, and delayed progression in treated groups [26,27,31,[34][35][36][37]. The main limitation of this approach in regard to clinical translatability is the low engraftment success and the high rate of stem cell death following transplantation.…”