You are here

| ESCs/iPSCs

Mouse Brain Transplantation Permits in vivo Imaging Analysis of Human Neuron Dynamics

Comment

Discuss

Review of “Mouse Brain Transplantation Permits in Vivo Analysis of Human iPSC-derived Neuron Dynamics” from Science by Stuart P. Atkinson 

The modeling of healthy and diseased human neuron dynamics currently faces several important obstacles. These include our inability to analyze live human tissues and the more general application of post-mortem tissues, the lack of phenotypic studies undertaken in a human genetic background rather than the mouse [1], and the absence of crucial interactions that diminish the utility of in vitro analyses using patient-specific human induced pluripotent stem cell (iPSC)-derived cells in advanced three-dimensional (3D) cultures [2].

With these problems in mind, researchers from the laboratories of Frederick J. Livesey (University of Cambridge, UK) and Vincenzo De Paola (Imperial College London, London, UK) hoped to build on previous transplantation work [3] and explore in real time the early expansion of human cortical tissue grafts from iPSC-derived neurons following transplantation into the mouse brain. The team´s new Science study employs single-cell-resolution intravital microscopy [4] for high-resolution analysis of both healthy and Down syndrome neuron dynamics in vivo [5].

Following transplantation into the cortex of an adult mouse, Real et al. demonstrated long-range axon growth of GFP-labelled hiPSC-derived neurons throughout the mouse adult brain and the formation of large vascularized neuron-glia areas of complex cytoarchitecture over the six-month experimental timeframe. Overall, these findings highlight the suitability of the adult mouse brain microenvironment to support the development of a multi-cellular transplant. 

Following the initial growth phase, longitudinal imaging established that branch-specific retraction, rather than degeneration, helped to refine developing human neurons. Investigations into human synaptic development determined that transplanted neurons formed synaptic structures within 4-12 weeks of development (akin to human fetal cerebral cortex), underwent synaptic reorganization, progressively increased dendritic spine density over one month, and balanced the rates of synaptic gain and loss over a time scale of few days. 

At the functional level, grafted neurons displayed excitability, fired action potentials, and received both excitatory and inhibitory inputs, suggestive of functional network connectivity. However, the study highlighted synaptic inputs to the grafted cells mainly from other human neurons, although inhibitory inputs likely proceeded from host neurons. Scrutiny of functional development of cortical networks revealed that the oscillatory population activity of the grafted human neurons mirrored the patterns of fetal neural networks.

Following the examination of healthy neuronal grafts, the authors next turned to transplants derived from Down syndrome patients. While the group observed normal developmental axon refinement, they also discovered a potential increase in spine density in DS cortical neurons, increased synaptic stability, and reduced neural network activity, thereby highlighting the potential of in vivo imaging of human tissue grafts for patient-specific modeling of cortical development, physiology, and pathogenesis.

This fascinating new in vivo imaging analysis of the development and maturation of human neurons in a suitable microenvironment has provided insight into pruning, synaptic refinement, and functional neural network formation, and this strategy will hopefully provide more insight into the mechanisms underlying neurodevelopmental disorders. 

For more on this exciting leap forward in the analysis of human neuron dynamics, stay tuned to the Stem Cells Portal.

References

  1. Espuny-Camacho I, Arranz AM, Fiers M, et al., Hallmarks of Alzheimer's Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain. Neuron 2017;93:1066-1081.e8.
  2. Carmeliet P and Tessier-Lavigne M, Common mechanisms of nerve and blood vessel wiring. Nature 2005;436:193.
  3. Thompson LH and Björklund A, Reconstruction of brain circuitry by neural transplants generated from pluripotent stem cells. Neurobiology of Disease 2015;79:28-40.
  4. Barbosa JS, Sanchez-Gonzalez R, Di Giaimo R, et al., Neurodevelopment. Live imaging of adult neural stem cell behavior in the intact and injured zebrafish brain. Science 2015;348:789-93.
  5. Real R, Peter M, Trabalza A, et al., In vivo modeling of human neuron dynamics and Down syndrome. Science 2018;362:eaau1810.