Intracerebroventricular Administration of Human Umbilical Cord Blood Cells Delays Disease Progression in Two Murine Models of Motor Neuron Degeneration

Abstract

The lack of effective drug therapies for motor neuron diseases (MND), and in general for all the neurodegenerative disorders, has increased the interest toward the potential use of stem cells. Among the cell therapy approaches so far tested in MND animal models, systemic injection of human cord blood mononuclear cells (HuCB-MNCs) has proven to reproducibly increase, although modestly, the life span of SOD1G93A mice, a model of familial amyotrophic lateral sclerosis (ALS), even if only few transplanted cells were found in the damaged areas. In attempt to improve the potential efficacy of these cells in the central nervous system, we examined the effect and distribution of Hoechst 33258-labeled HuCB-MNCs after a single bilateral intracerberoventricular injection in two models of motor neuron degeneration, the transgenic SOD1G93A and wobbler mice. HuCB-MNCs significantly ameliorated symptoms progression in both mouse models and prolonged survival in SOD1G93A mice. They were localized in the lateral ventricles, even 4 months after administration. However, HuCB-MNCs were not found in the spinal cord ventral horns. This evidence strengthens the hypothesis that the beneficial role of transplanted cells is not due to cell replacement but is rather associated with the production and release of circulating protective factors that may act both at the central and/or peripheral levels. In particular, we show that HuCB-MNCs release a series of cytokines and chemokines with antiinflammatory properties that could be responsible of the functional improvement of mouse models of motor neuron degenerative disorders.

Wharton's jelly derived mesenchymal stromal cells: Biological properties, induction of neuronal phenotype and current applications in neurodegeneration research

“…Again, and in keeping with previous findings (Bigini et al, 2011), the appearance of transplanted cells, never showing morphological features of mature neurons, nor expressing any neuronal markers either, strongly suggest that, as outlined above, they may act via the production and release of locally acting factors with protective and/or anti-inflammatory properties, rather than by replacement of degenerating neurons.…”

“…This provides support to the hypothesis that the restoring effects of transplanted cells in not due to cell replacement per se but, rather, it is associated with the production and release of circulating protective factors that may act both ad the CNS and PNS levels. In fact it has been shown that implanted MSCs release a series of cytokines and chemokines with anti-inflammatory properties that could be responsible of the functional improvement of mouse models of motor neuron degenerative disorder (Bigini et al, 2011;Uccelli et al, 2012).…”

Longitudinal Tracking of Human Fetal Cells Labeled with Super Paramagnetic Iron Oxide Nanoparticles in the Brain of Mice with Motor Neuron Disease

“…As a matter of fact we have already demonstrated that ICV injection of SCs in two different ALS animal models (SOD1G93A and wobbler mice) resulted in significant therapeutic improvements although no cell localization in the pathological tissue was observed [6]. Moreover, intrathecal and intravenous SC administration have already been tested in a preliminary clinical trial aimed at demonstrating the safety and immunological effects of mesenchymal SC transplantation in patients with multiple sclerosis and ALS [34].…”

Cultivating stem cells for treating amyotrophic lateral sclerosis

“…The route of administration of stem cells needs to be pre-determined: systemic [21] , intracerberoventricular [22] , and local injection [23][24][25][26][27][28] . Upon systemic injection, transplanted stem cells migrated to the damaged areas in SOD1G93A mice [22] .…”

“…Upon systemic injection, transplanted stem cells migrated to the damaged areas in SOD1G93A mice [22] . Neural precursor cells transplanted specifically into the cervical spinal cord ventral gray matter of both SOD1G93A rats survived [29] .…”