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Summary: Astrocytes from familial amyotrophic lateral sclerosis (ALS) patients or transgenic mice are toxic specifically to motor neurons (MNs). It is not known if astrocytes from sporadic ALS (sALS) patients cause MN degeneration in vivo and whether the effect is specific to MNs. By transplanting spinal neural progenitors, derived from sALS and healthy induced pluripotent stem cells (iPSCs), into the cervical spinal cord of adult SCID mice for 9 months, we found that differentiated human astrocytes were present in large areas of the spinal cord, replaced endogenous astrocytes, and contacted neurons to a similar extent. Mice with sALS but not non-ALS cells showed reduced non-MNs numbers followed by MNs in the host spinal cord. The surviving MNs showed reduced inputs from inhibitory neurons and exhibited disorganized neurofilaments and aggregated ubiquitin. Correspondingly, mice with sALS but not non-ALS cells showed declined movement deficits. Thus, sALS iPSC-derived astrocytes cause ALS-like degeneration in both MNs and non-MNs. : In this article, Zhang, Chen, and colleagues show that in the chimeric model created by transplanting human iPSC-derived neural progenitors into the adult mouse spinal cord, sALS astrocytes induced ALS-like degeneration in non-MNs followed by MNs. The results demonstrate the causal role of sALS astrocytes in vivo and suggest the role of non-MNs in mediating MN degeneration. Keywords: amyotrophic lateral sclerosis, induced pluripotent stem cells, astrocytes, motor neurons, interneurons, cell transplantation, chimera, neuron-glial interaction