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Human-derived neural progenitors functionally replace astrocytes in adult mice
Hong Chen, … , Melvin Ayala, Su-Chun Zhang
Hong Chen, … , Melvin Ayala, Su-Chun Zhang
Published February 2, 2015
Citation Information: J Clin Invest. 2015;125(3):1033-1042. https://doi.org/10.1172/JCI69097.
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Technical Advance Neuroscience

Human-derived neural progenitors functionally replace astrocytes in adult mice

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Abstract

Astrocytes are integral components of the homeostatic neural network as well as active participants in pathogenesis of and recovery from nearly all neurological conditions. Evolutionarily, compared with lower vertebrates and nonhuman primates, humans have an increased astrocyte-to-neuron ratio; however, a lack of effective models has hindered the study of the complex roles of human astrocytes in intact adult animals. Here, we demonstrated that after transplantation into the cervical spinal cords of adult mice with severe combined immunodeficiency (SCID), human pluripotent stem cell–derived (PSC-derived) neural progenitors migrate a long distance and differentiate to astrocytes that nearly replace their mouse counterparts over a 9-month period. The human PSC-derived astrocytes formed networks through their processes, encircled endogenous neurons, and extended end feet that wrapped around blood vessels without altering locomotion behaviors, suggesting structural, and potentially functional, integration into the adult mouse spinal cord. Furthermore, in SCID mice transplanted with neural progenitors derived from induced PSCs from patients with ALS, astrocytes were generated and distributed to a similar degree as that seen in mice transplanted with healthy progenitors; however, these mice exhibited motor deficit, highlighting functional integration of the human-derived astrocytes. Together, these results indicate that this chimeric animal model has potential for further investigating the roles of human astrocytes in disease pathogenesis and repair.

Authors

Hong Chen, Kun Qian, Wei Chen, Baoyang Hu, Lisle W. Blackbourn IV, Zhongwei Du, Lixiang Ma, Huisheng Liu, Karla M. Knobel, Melvin Ayala, Su-Chun Zhang

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Figure 2

Human neural progenitors differentiate into astrocytes and replace endogenous astrocytes.

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Human neural progenitors differentiate into astrocytes and replace endog...
(A and B) hGFAP-expressing astrocytes began to appear at 3 months and became the predominant population by 9 months. (A) The GFP overlapped with (B) hGFAP at 5 and 9 months. (C) The longitudinal distribution of hGFAP-expressing astrocytes (red) as well as endogenous astrocytes (green) in the spinal cord. Scale bar: 500 μm. (D) Human astrocytes (from iPSCs) in the gray matter and white matter exhibit typical astrocyte morphologies. Scale bar: 50 μm. (E) Quantification (mean ± SEM) of all astrocytes (GFAP+) in the transplanted and nontransplanted sides (n = 3, P > 0.05, t test), and the average population of mouse astrocytes (GFAP+/hGFAP–) and human astrocytes (GFAP+/hGFAP+) in the grafted spinal cord at 9 months.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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