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Imaging the Integration of Transplanted Neurons in the Lesioned Brain

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Review of “Transplanted embryonic neurons integrate into adult neocortical circuits” from Nature by Stuart P. Atkinson

While the transplantation of neural cells into the brain represents an exciting strategy to combat host neuron loss due to injury or disease [1, 2], we are still unsure to what extent transplanted cells can integrate into the hosts neural circuitry.

New research from the laboratories of Magdalena Götz and Mark Hübener aimed to answer this question by following the consequences of embryonic neurons transplanted into a lesion within the adult mouse visual cortex employing complex in vivo imaging techniques. The results of this study, published in Nature, suggests that grafted cells DO integrate and  become indistinguishable from host neurons [3]. 

The study employed a selective lesion methodology [4] followed by the implantation of fluorescently labeled donor cells at around 7 to 10 days later and assessment via repeated two-photon imaging [5]. This technique established that the transplanted cells acquired morphologies typical of visual cortex pyramidal cells and formed structures correlating to synapse formation within 4-8 weeks. Moreover, transplanted cells grow axons which reach expected target areas while modified rabies virus (RABV)-based monosynaptic tracing [6] demonstrated endogenous levels of input from host neurons.

So transplanted cells seem to integrate well into the visual cortex, but can they process visual inputs? Again employing two-photon imaging to assess the responses of single transplanted cells to visual stimuli, the authors observed strong evidence of maturing functional integration over time (2 – 3 months) with responses becoming indistinguishable from those of host neurons.

Overall, this exciting imaging study (see the original paper for some extensive and stunning neural imaging) strongly suggests that transplanted neurons can integrate into the host circuitry and can quickly mature and reconnect to attain required functionality. Can neural cells derived from human pluripotent stem cell sources also integrate into the visual cortex, or any other brain region, with as much success? Stay tuned to Stem Cells and the Stem Cells Portal to find out.

References

  1. Lindvall O, Kokaia Z, and Martinez-Serrano A. Stem cell therapy for human neurodegenerative disorders-how to make it work. Nat Med 2004;10 Suppl:S42-50.
  2. Thompson LH and Bjorklund A. Reconstruction of brain circuitry by neural transplants generated from pluripotent stem cells. Neurobiol Dis 2015;79:28-40.
  3. Falkner S, Grade S, Dimou L, et al. Transplanted embryonic neurons integrate into adult neocortical circuits. Nature 2016;539:248-253.
  4. Madison RD and Macklis JD. Noninvasively induced degeneration of neocortical pyramidal neurons in vivo: selective targeting by laser activation of retrogradely transported photolytic chromophore. Exp Neurol 1993;121:153-159.
  5. Holtmaat A, Bonhoeffer T, Chow DK, et al. Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window. Nat Protoc 2009;4:1128-1144.
  6. Wickersham IR, Lyon DC, Barnard RJ, et al. Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 2007;53:639-647.