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Exploring Human Stem Cell Therapies for Cerebral Cortex Disorders in Human Organotypic Culture

Review of "Grafted human pluripotent stem cell-derived cortical neurons integrate into adult human cortical neural circuitry" from STEM CELLS Translational Medicine by Stuart P. Atkinson

Recent studies from the laboratory of Zaal Kokaia (Lund University, Sweden) demonstrated that the transplantation of cortically fated human induced pluripotent stem (iPSC)‐derived long‐term neuroepithelial‐like stem cells into the brain of a rat model of cortical stroke led to cell engraftment and improvements in sensorimotor deficits [1-3]. While these findings provided evidence for the potential efficacy of human iPSC-based therapeutics for cerebral cortex disorders, nearly all relevant studies have been carried out in animal models [4], and so, the in vivo fate of iPSC-derived neurons in the human cortex remains relatively unknown.

Now, researchers from the Kokaia lab return with a new STEM CELLS Translational Medicine study that explored the interaction of cortically fated human iPSC-derived long‐term neuroepithelial‐like stem cells with organotypic slice cultures derived from the adult human cortex [5]. Hansen et al. now report the functional engraftment of human iPSC-derived neurons into human adult host neural networks in a study that may provide the basis for the clinical translation of iPSC-based therapeutics for cerebral cortex disorders.

The authors discovered that transplantation onto the adult human cortex slices obtained from epileptic patients undergoing resection surgery prompted the differentiation of human iPSC‐derived long‐term neuroepithelial‐like stem cells into mature layer‐specific cortical neurons over four to eight weeks in culture. Encouragingly, the study failed to note any teratoma or secondary tumor formation, thereby suggesting the safety of human iPSC-derived long‐term neuroepithelial‐like stem cells. 

The authors then employed a range of approaches, including immuno‐electron microscopy, rabies virus retrograde monosynaptic tracing, and whole‐cell patch‐clamp recordings, to demonstrate that human iPSC‐derived long‐term neuroepithelial‐like stem cell‐derived cortical neurons exhibited the morphological features of mature neurons, formed afferent and efferent synapses with the adult human cortical neurons present in the adult human cortex slices, and functionally integrated into the host neural network.

Overall, the authors provide ample evidence that human iPSC-derived neurons can functionally integrate into a human adult host neural network, and in doing so, moves the field one step closer to the clinical translation of patient-specific neuronal replacement strategies that promote functional recovery in patients with brain injuries or those suffering from cerebral cortex disorders.

For more on the therapeutic application of human iPSCs and their derivatives, stay tuned to the Stem Cells Portal!

References

  1. Tornero D, Wattananit S, Grønning Madsen M, et al., Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery. Brain 2013;136:3561-3577.
  2. Palma-Tortosa S, Tornero D, Grønning Hansen M, et al., Activity in grafted human iPS cell–derived cortical neurons integrated in stroke-injured rat brain regulates motor behavior. Proceedings of the National Academy of Sciences 2020;117:9094.
  3. Tornero D, Tsupykov O, Granmo M, et al., Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli. Brain 2017;140:692-706.
  4. Lindvall O, Treatment of Parkinson's disease using cell transplantation. Philosophical Transactions of the Royal Society B: Biological Sciences 2015;370:20140370.
  5. Grønning Hansen M, Laterza C, Palma-Tortosa S, et al., Grafted human pluripotent stem cell-derived cortical neurons integrate into adult human cortical neural circuitry. STEM CELLS Translational Medicine 2020;9:1365-1377.