Abstract
SummaryAstrocytes 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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disease characterized by a progressive loss of motor neurons (MNs) in the cerebral cortex, brainstem, and spinal cord
The role of mutant protein-expressing astrocytes in ALS pathogenesis is further demonstrated by compromised survival of mouse or human embryonic stem cell-derived MNs when co-cultured with astrocytes that are isolated from SOD1G93A transgenic mice (Di Giorgio et al, 2007; Nagai et al, 2007) or those expressing SOD1G37R protein (Marchetto et al, 2008)
We have recently shown that ALS (SOD1D90A) patient-induced pluripotent stem cell-derived neural progenitors, following transplantation into the spinal cord of severe combined immunodeficiency (SCID) mice and differentiation to astrocytes, impair the survival of MNs (Chen et al, 2015)
Summary
Astrocytes from familial amyotrophic lateral sclerosis (ALS) patients or transgenic mice are toxic 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. The surviving MNs showed reduced inputs from inhibitory neurons and exhibited disorganized neurofilaments and aggregated ubiquitin. SALS iPSC-derived astrocytes cause ALS-like degeneration in both MNs and non-MNs
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