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Directly Programmed Neurons Provide Boost for Chemotherapy‐induced Neuropathy Research

Review of “Chemotherapy‐Induced Neuropathy and Drug Discovery Platform Using Human Sensory Neurons Converted Directly from Adult Peripheral Blood” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Chemotherapy-induced peripheral neuropathy (CIPN) causes weakness, numbness, and pain in patients [1, 2], and, unfortunately, current treatments are limited to generic pain medication. A deeper understanding of CIPN pathophysiology may provide new and effective therapeutic approaches [2], although much of the research in this field has been restricted to rodent models, with the nociceptive sensory neurons involved exhibiting many notable differences between rodents and humans [3].

Researchers led by Tony J. Collins and Mickie Bhatia (McMaster University, Hamilton, Ontario, Canada) hoped to provide impetus to human-specific CIPN research through the development of a drug screening system using large numbers of induced sensory neurons (iSNs) reprogrammed directly from non-mobilized human adult peripheral blood (PB) [4]. Overall, this new STEM CELLS Translational Medicine study aims to provide the base for the generation of more robust high‐throughput screens and the discovery of new strategies to prevent or provide treatments for CIPN in humans.

Vojnits et al. employed non-mobilized cryogenically preserved PB as a practical and readily-available starting point to produce iSNs. Firstly, the authors induced the rare CD34+ hematopoietic stem/progenitor cells present in PB into a massive quantity of induced neural progenitor cells (iNPCs) through the lentiviral delivery of the OCT4 pluripotency-associated gene combined with inhibition of SMAD and GSK‐3 signaling pathways [5, 6] and further expansion under optimized conditions. The authors estimated that 200 ml of PB provided for the generation of 10 × 109 iNPCs that could be frozen and stored without a significant loss of subsequent differentiation potential.

Treatment with a small‐molecule inhibitor cocktail then induced high yield differentiation into a pure population of mature iSNs [5] that expressed generic and nociceptor-specific neuronal markers and exhibited expected nociceptive functions. The overall process, from PB to functional induced sensory neurons, took around thirty days, a process notably quicker than the conventional strategy of induced pluripotent stem cell generation from PB and their subsequent differentiation towards sensory neurons.

The next phase adapted the culture of iSNs to 96‐well plate culture with the help of Rho/Rho‐kinase pathway inhibition to promote cell survival during seeding and maintain their mature phenotype and then tested responses following exposure to compounds associated with CIPN [5] in the hope of encountering the expected responses, thereby validating this approach. Encouragingly, four of the five tested compounds reduced neurite length in the absence of cytotoxicity in cells treated one day after seeding, and promoted neurite degeneration, the clinical “biomarker” of CIPN, in cells treated seven days after seeding.

The authors believe that the platform described in this new study can be applied to high throughput screens for the discovery of drugs that can prevent, block, or repair CIPN damage in humans; however, human iSNs derived from PB may also find use in the exploration of the mechanisms of action behind neurodevelopmental disorders and the identification of new human-specific targets of nociceptive control.

For more on how induced sensory neuron-based high throughput screens may provide a boost to the pursuit of treatments for chemotherapy-induced peripheral neuropathy, stay tuned to the Stem Cells Portal!

References

  1. Lema MJ, Foley KM, and Hausheer FH, Types and Epidemiology of Cancer-Related Neuropathic Pain: The Intersection of Cancer Pain and Neuropathic Pain. The Oncologist 2010;15:3-8.
  2. Addington J and Freimer M, Chemotherapy-induced peripheral neuropathy: an update on the current understanding. F1000Research 2016;5.
  3. Davidson S, Copits BA, Zhang J, et al., Human sensory neurons: Membrane properties and sensitization by inflammatory mediators. Pain 2014;155:1861-1870.
  4. Vojnits K, Mahammad S, Collins TJ, et al., Chemotherapy-Induced Neuropathy and Drug Discovery Platform Using Human Sensory Neurons Converted Directly from Adult Peripheral Blood. STEM CELLS Translational Medicine 2019;8:1180-1191.
  5. Lee J-H, Mitchell Ryan R, McNicol Jamie D, et al., Single Transcription Factor Conversion of Human Blood Fate to NPCs with CNS and PNS Developmental Capacity. Cell Reports 2015;11:1367-1376.
  6. Mitchell RR, Szabo E, Benoit YD, et al., Activation of Neural Cell Fate Programs Toward Direct Conversion of Adult Human Fibroblasts into Tri-Potent Neural Progenitors Using OCT-4. Stem Cells and Development 2014;23:1937-1946.