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3D Scaffolds – The Way Forward for Improved Neural Therapies?

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Review of “Generation and transplantation of reprogrammed human neurons in the brain using 3D microtopographic scaffolds” from Nature Communications by Stuart P. Atkinson

The transplantation of reprogrammed neurons produced from donor cells aims to provide patient-specific treatments for a wide range of neurodegenerative diseases and brain injuries [1, 2]. However, as Zhiping P. Pang and Prabhas V. Moghe note, we lacked a method to grow and transplant neurons into the brain in an appropriate three-dimensional (3D) configuration where they will survive and integrate into the host’s neural network.

Their new study, published in Nature Communications, describes their recent studies into neural cells produced via the overexpression of the neural transcription factor NeuroD1 in fibroblasts (iN Cells) [3] grown on (and around!) three dimensional electrospun synthetic polymer fibre constructs. Excitingly, they show that their methodology enhances iN cell survival, engraftment, and overall functionality and, therefore, could represent an interesting new therapeutic strategy. 

NeuroD1 transduction of human fibroblasts in standard two-dimensional culture conditions created iN cells which expressed mature neuronal markers, exhibited complex neuronal morphologies, and displayed some level of electrophysiological functionality. Part one accomplished!

Part two investigated whether 3D electrospun fibrous substrates made of pDTEc (that’s poly(desaminotyrosyl tyrosine ethyl ester carbonate to all you chemists) [4, 5] could support improved iN maturation and functionality. Comparisons demonstrated that iN cells grown on 3D electrospun fibres exhibited complex morphology with extensive neurite outgrowth and expressed neuron markers in a similar manner to iN cells produced on 2D substrates. However, the 3D fibrous substrates selectively reduced the presence of residual iPSCs, enhanced 3D organization, and improved cell–cell contacts, all leading to a boost in functional and phenotypic maturity.

The final part of the study looked at the in vivo consequences of iN cells growth on microscale electrospun fibres. Initial transplantation into mouse organotypic hippocampal slice cultures (ex vivo) demonstrated enhanced engraftment and functionality as compared to transplantation of dissociated iN cells, and the authors sought to confirm these findings in vivo following transplantation into the mouse striatum. Excitingly, this demonstrated that scaffold-supported iN cells survived better than dissociated iN cells with some signs of integration into the host’s neural network also noted.

3D growth recapitulates the in vivo settings, and so it should come as no great surprise that iN cells grown on 3D microscale biomaterials should lead to the encouraging results observed in this study. The authors hope that this prototype biomaterial can be advanced to accommodate the growth, survival, and function of a plethora of neural cells and so, provide broad neuro-regenerative relevance towards ameliorating neurodegenerative dysfunction and central nervous system injuries.

References

  1. Hibaoui Y and Feki A Human pluripotent stem cells: applications and challenges in neurological diseases. Front Physiol 2012;3:267.
  2. Burns TC and Steinberg GK Stem cells and stroke: opportunities, challenges and strategies. Expert Opin Biol Ther 2011;11:447-461.
  3. Carlson AL, Bennett NK, Francis NL, et al. Generation and transplantation of reprogrammed human neurons in the brain using 3D microtopographic scaffolds. Nat Commun 2016;7:10862.
  4. Carlson AL, Florek CA, Kim JJ, et al. Microfibrous substrate geometry as a critical trigger for organization, self-renewal, and differentiation of human embryonic stem cells within synthetic 3-dimensional microenvironments. FASEB J 2012;26:3240-3251.
  5. Hooper KA, Macon ND, and Kohn J Comparative histological evaluation of new tyrosine-derived polymers and poly (L-lactic acid) as a function of polymer degradation. J Biomed Mater Res 1998;41:443-454.