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Long-term Neuronal Cell Transplant Study Highlights Long-Distance Neural Growth

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Review of “Long-Distance Axonal Growth and Protracted Functional Maturation of Neurons Derived From Human Induced Pluripotent Stem Cells after Intracerebral Transplantation” from STEM CELLS Translational Medicine by Stuart P. Atkinson

The in vitro differentiation of induced pluripotent stem cells (iPSCs) into a range of patient-specific neural cells has met with great success. However, a lack of detailed information on the functional and anatomical characteristics of iPSC-derived neural grafts in donors has limited the translation of in vitro success to in vivo treatments for various diseases and disorders. 

Researchers from the laboratory of Lachlan Thompson (Florey Institute for Neuroscience and Mental Health, Victoria, Australia) hope to alter this in their recent STEM CELLS Translational Medicine study. Niclis et al describe the application of a human iPSC line expressing green fluorescent protein (GFP) as a useful tool in the characterization of neural grafts. Their long-term studies in athymic rats now provide detailed information on the electrophysiological development and anatomical patterns of long-distance axonal growth in the host brain [1].

Prior to transplantation into the striatum of female athymic rats, the authors first differentiated the GFP-iPSCs into early Sox2+/Vimentin+ neural progenitors. Subsequent fluorescence analysis of coronal brain slices evidenced both the persistence of the GFP signal throughout the 50-week analysis and the progressive electrophysiological and morphological maturation of the iPSC-derived neural graft in vivo. However, this maturation occurred over a timescale of months rather than weeks, with a shorter timescale more common in studies of this kind.

A ~20-fold increase in cell number over the 50 weeks suggested significant proliferation and net growth following transplantation and GFP analysis demonstrated the presence of a mixture of actively dividing immature progenitors and migrative mature neuronal/glial cells. Strikingly, the authors also noted the establishment of extensive patterns of long-distance axonal growth throughout the fully developed host brain, especially along host white matter corridors where innervation of specific host nuclei predominated.

The adjoined figure depicts the long-distance growth of grafted GFP+ neurons throughout the host brain at 50 weeks. The top two depicts coronal sections, the bottom row depicts horizontal sections, and the graft appears as a black deposit in the corpus callosum (ii) or the striatum and overlying cortex (v & vi).

Over the short-term, many studies have suggested that neural cell transplants may induce some form of regenerative response to aid recovery from neurological afflictions. However, while this new study supports the feasibility of the reconstitution of long-distance neuronal circuitry and functional recovery by cell transplantation, these processes may only occur over long time-periods. Therefore, these findings may help to guide the scheduling of post-transplantation observation times in pre-clinical studies aimed at treating animal models of brain injury.

For the long view on cell transplantation in the brain, keep the Stem Cells Portal bookmarked!

References

  1. Niclis JC, Turner C, Durnall J, et al. Long-Distance Axonal Growth and Protracted Functional Maturation of Neurons Derived from Human Induced Pluripotent Stem Cells After Intracerebral Transplantation. STEM CELLS Translational Medicine 2017;6:1547-1556.