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

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 4

Human astrocytes structurally integrate into the host tissue.

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Human astrocytes structurally integrate into the host tissue. (A) In the...
(A) In the gray matter, the hGFAP+ astrocytes (from iPSCs) presented with a star-shaped morphology, surrounding neurons, including ChAT+ MNs (inset). (B) In the white matter, the human astrocytes (from iPSCs) extended long processes that line up with the neurofilament-positive (NF+) axons. (C) The distribution of GLT1 is similar between the transplanted side and the untransplanted side, with a higher density in the gray matter than in the white matter. (D) In the gray matter, CX43 was predominantly in the hGFAP+ astrocyte processes, especially in the area surrounding neuronal cell bodies. (E) In the white matter, CX43 immunoreactivity was present in the cytoplasm. (F) Human astrocytes (GFP+/GFAP+, from ESCs) projected to the blood vessel, with their end feet closely surrounding the blood vessel. (G) The AQP4 signals were largely concentrated on the astrocytic end feet along the vessels. Scale bar: 50 μm (A–C); 10 μm (D–G).