Microglia are the resident macrophages of the CNS and execute crucial functions for the maintenance of neuronal homeostasis, for instance, by providing nurture and support to neurons via secretion of soluble factors, clearance of dead cells or misfolded proteins, and protection from infectious agents 10. In particular, a wealth of evidence supports a role for microglia, ranging from early post mortem and imaging studies 6, 7 to recent biomarker investigations in which microglia-associated inflammatory markers were elevated in the cerebrospinal fluid of ALS samples 8, 9. In addition to dysregulated MN-intrinsic pathways, e.g., oxidative stress or protein aggregation 4, there is broad consensus that non-neuronal cells orchestrate a complex neuroinflammatory process in the central nervous system (CNS) of ALS patients 5. Experimental evidence for ALS supports a pathophysiological model in which a combination of cell-autonomous and non-cell-autonomous factors leads to MN demise 1, 2, 3. Motor neuron (MN) diseases such as amyotrophic lateral sclerosis (ALS) are primarily characterized by the degeneration of cortical, brainstem, and spinal cord MNs, resulting in progressive paralysis and premature death. This novel and authentic human model system facilitates the study of physiological motor neuron-microglia crosstalk and will allow the investigation of non-cell-autonomous phenotypes in motor neuron diseases such as amyotrophic lateral sclerosis. Further, they express key amyotrophic lateral sclerosis-associated genes and release disease-relevant biomarkers. Co-cultured microglia express key identity markers and transcriptomically resemble primary human microglia, have highly dynamic ramifications, are phagocytically competent, release relevant cytokines and respond to stimulation. Here, we combine both cell lineages and establish a novel co-culture of iPSC-derived spinal motor neurons and microglia, which is compatible with motor neuron identity and function. In previous work, we have established protocols for the differentiation of iPSC-derived spinal motor neurons and microglia.

Motor neuron diseases such as amyotrophic lateral sclerosis are primarily characterized by motor neuron degeneration with additional involvement of non-neuronal cells, in particular, microglia.

Batch pdf merger key gen