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Supportive Microcarriers Boost Stem Cell-Based Therapy for Parkinson ’s disease

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Review of “Survival, Differentiation, and Neuroprotective Mechanisms of Human Stem Cells Complexed With Neurotrophin-3-Releasing Pharmacologically Active Microcarriers in an Ex Vivo Model of Parkinson’s Disease” from Stem Cells TM by Stuart P. Atkinson

Stem cell-based therapies for neurodegenerative disease have assessed numerous different types of stem cells with varying levels of success. Clinical trials using mesenchymal and neuronal stem cells (MSCs and NSCs) for the treatment of Parkinson’s disease (PD) have found some stem cell mediated-improvements, but are beset by problems such as low cell survival, differentiation and engraftment [1, 2].  To address these problems, researchers from the laboratory of Claudia N. Montero-Menei (INSERM, France) investigated a potential role for pharmacologically active microcarriers (PAMs). These provide a three-dimensional biomimetic support to cells and mediate the sustained release of cytokines, and so may improve stem cell-based PD therapy. In their recently published study in Stem Cells Translational Medicine, they show that PAMs loaded with neurotrophin-3 (NT3) aid survival, differentiation and neuroprotection of NSCs and marrow-isolated adult multilineage inducible (MIAMI) cells [3] in a rat model of PD [4].

In order to better understand the in vivo effects of various therapeutic approaches the group used organotypic cultures made from rat brain slices as a model for PD [5, 6]. Both NSCs and MIAMI cells expressed the receptor for NT3 and, after culture and adherence to the PAM surface (~94% efficiency; See figure), the researchers added the PAM-cell complexes to the brain slice culture 2 days after their formation and the start of nigrostriatal pathway degeneration, the pathway affected in PD.

Analysis at 16 days found that while PAM alone and PAM-NSCs inhibited the reduction in rat dopaminergic neuron density observed in the nigrostriatal bundle, PAM-MIAMI application significantly curbed this reduction. PAM-NSC and PAM-MIAMI also inhibited neuron loss in the medial forebrain bundle (MFB), although only PAM-NSCs mediated an improvement of dopamine levels. At this stage, NSC and MIAMI cells had morphologically changed from a round stem cell-like shape, to a neuron-like morphology with significant neurite outgrowth (NSCs) and a bipolar- like morphology (MIAMI). GFP-labelling allowed the researchers to demonstrate that while PAM-NT3 did not aid NSC survival, PAM-NT3 did boost MIAMI cells survival by 2- to 3-fold. Additionally, PAM-NT3 induced the differentiation of NSCs and MIAMI cells to b3- tubulin-positive neuronal cells, although the number of neurons was always higher for NSCs. Finally, human-specific TH labelling found that PAM-NT3 also induced a greater level of differentiation towards a dopaminergic fate, although this was not significant for MIAMI cells.

This all suggests that PAMs carrying specific cargoes may aid in the future clinical application of NSCs or MIAMI cells in neurodegenerative diseases. NT3 seems to boots the innate properties of the PAM-adhered stem cells to protect and support endogenous cells, while also promoting exogenous stem cells to differentiate into dopaminergic neurons. Future studies may look to analyze the additive effects or using both cell types at the same time, or the identification of a cocktail of factors to promote further therapeutic effects.

References

  1. Lazic SE and Barker RA The future of cell-based transplantation therapies for neurodegenerative disorders. J Hematother Stem Cell Res 2003;12:635-642.
  2. Lescaudron L, Naveilhan P, and Neveu I The use of stem cells in regenerative medicine for Parkinson's and Huntington's Diseases. Curr Med Chem 2012;19:6018-6035.
  3. D'Ippolito G, Diabira S, Howard GA, et al. Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. Journal of cell science 2004;117:2971-2981.
  4. Daviaud N, Garbayo E, Sindji L, et al. Survival, differentiation, and neuroprotective mechanisms of human stem cells complexed with neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo model of Parkinson's disease. Stem Cells Translational Medicine 2015;4:670-684.
  5. Daviaud N, Garbayo E, Schiller PC, et al. Organotypic cultures as tools for optimizing central nervous system cell therapies. Experimental neurology 2013;248:429-440.
  6. Daviaud N, Garbayo E, Lautram N, et al. Modeling nigrostriatal degeneration in organotypic cultures, a new ex vivo model of Parkinson's disease. Neuroscience 2014;256:10-22.