Recent insights from human induced pluripotent stem cell models into the role of microglia in amyotrophic lateral sclerosis

doi:10.1002/bies.202400054

Review

. 2024 Jul;46(7):e2400054.

doi: 10.1002/bies.202400054. Epub 2024 May 7.

Recent insights from human induced pluripotent stem cell models into the role of microglia in amyotrophic lateral sclerosis

Lara M Nikel^{1

2}, Kevin Talbot^{1

2}, Björn F Vahsen^{1

2}

Affiliations

¹ Oxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
² Dorothy Crowfoot Hodgkin Building, Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.

PMID: 38713169
DOI: 10.1002/bies.202400054

Review

Recent insights from human induced pluripotent stem cell models into the role of microglia in amyotrophic lateral sclerosis

Lara M Nikel et al. Bioessays. 2024 Jul.

. 2024 Jul;46(7):e2400054.

doi: 10.1002/bies.202400054. Epub 2024 May 7.

Authors

Lara M Nikel^{1

2}, Kevin Talbot^{1

2}, Björn F Vahsen^{1

2}

Affiliations

¹ Oxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
² Dorothy Crowfoot Hodgkin Building, Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.

PMID: 38713169
DOI: 10.1002/bies.202400054

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, primarily leading to the degeneration of motor neurons. The traditional focus on motor neuron-centric mechanisms has recently shifted towards understanding the contribution of non-neuronal cells, such as microglia, in ALS pathophysiology. Advances in induced pluripotent stem cell (iPSC) technology have enabled the generation of iPSC-derived microglia monocultures and co-cultures to investigate their role in ALS pathogenesis. Here, we briefly review the insights gained from these studies into the role of microglia in ALS. While iPSC-derived microglia monocultures have revealed intrinsic cellular dysfunction due to ALS-associated mutations, microglia-motor neuron co-culture studies have demonstrated neurotoxic effects of mutant microglia on motor neurons. Based on these findings, we briefly discuss currently unresolved questions and how they could be addressed in future studies. iPSC models hold promise for uncovering disease-relevant pathways in ALS and identifying potential therapeutic targets.

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References

REFERENCES

1. Vahsen, B. F., Gray, E., Thompson, A. G., Ansorge, O., Anthony, D. C., Cowley, S. A., Talbot, K., & Turner, M. R. (2021). Non‐neuronal cells in amyotrophic lateral sclerosis—from pathogenesis to biomarkers. Nature Reviews Neurology, 17, 333–348.
1. Kerk, S. Y., Bai, Y., Smith, J., Lalgudi, P., Hunt, C., Kuno, J., Nuara, J., Yang, T., Lanza, K., Chan, N., Coppola, A., Tang, Q., Espert, J., Jones, H., Fannell, C., Zambrowicz, B., & Chiao, E. (2022). Homozygous ALS‐linked FUS P525L mutations cell‐ autonomously perturb transcriptome profile and chemoreceptor signaling in human iPSC microglia. Stem Cell Reports, 17, 678–692.
1. Funes, S., Jung, J., Gadd, D. H., Mosqueda, M., Mosqueda, M., Zhong, J., Shankaracharya Unger, M., Stallworth, K., Cameron, D., Rotunno, M. S., Dawes, P., Fowler‐Magaw, M., Keagle, P. J., McDonough, J. A., Boopathy, S., Sena‐Esteves, M., Nickerson, J. A., Lutz, C., Skarnes, W. C., … Bosco, D. A. (2024). Expression of ALS‐PFN1 impairs vesicular degradation in iPSC‐derived microglia. Nature Communications, 15, 2497.
1. Giacomelli, E., Vahsen, B. F., Calder, E. L., Xu, Y., Scaber, J., Gray, E., Dafinca, R., Talbot, K., & Studer, L. (2022). Human stem cell models of neurodegeneration: From basic science of amyotrophic lateral sclerosis to clinical translation. Cell Stem Cell, 29, 11–35.
1. Vahsen, B. F., Nalluru, S., Morgan, G. R., Farrimond, L., Carroll, E., Xu, Y., Cramb, K. M. L., Amein, B., Scaber, J., Katsikoudi, A., Candalija, A., Carcolé, M., Dafinca, R., Isaacs, A. M., Wade‐Martins, R., Gray, E., Turner, M. R., Cowley, S. A., & Talbot, K. (2023). C9orf72‐ALS human iPSC microglia are pro‐inflammatory and toxic to co‐cultured motor neurons via MMP9. Nature Communications, 14, 5898.

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[1] Vahsen, B. F., Gray, E., Thompson, A. G., Ansorge, O., Anthony, D. C., Cowley, S. A., Talbot, K., & Turner, M. R. (2021). Non‐neuronal cells in amyotrophic lateral sclerosis—from pathogenesis to biomarkers. Nature Reviews Neurology, 17, 333–348.

[2] Vahsen, B. F., Gray, E., Thompson, A. G., Ansorge, O., Anthony, D. C., Cowley, S. A., Talbot, K., & Turner, M. R. (2021). Non‐neuronal cells in amyotrophic lateral sclerosis—from pathogenesis to biomarkers. Nature Reviews Neurology, 17, 333–348.

[3] Kerk, S. Y., Bai, Y., Smith, J., Lalgudi, P., Hunt, C., Kuno, J., Nuara, J., Yang, T., Lanza, K., Chan, N., Coppola, A., Tang, Q., Espert, J., Jones, H., Fannell, C., Zambrowicz, B., & Chiao, E. (2022). Homozygous ALS‐linked FUS P525L mutations cell‐ autonomously perturb transcriptome profile and chemoreceptor signaling in human iPSC microglia. Stem Cell Reports, 17, 678–692.

[4] Kerk, S. Y., Bai, Y., Smith, J., Lalgudi, P., Hunt, C., Kuno, J., Nuara, J., Yang, T., Lanza, K., Chan, N., Coppola, A., Tang, Q., Espert, J., Jones, H., Fannell, C., Zambrowicz, B., & Chiao, E. (2022). Homozygous ALS‐linked FUS P525L mutations cell‐ autonomously perturb transcriptome profile and chemoreceptor signaling in human iPSC microglia. Stem Cell Reports, 17, 678–692.

[5] Funes, S., Jung, J., Gadd, D. H., Mosqueda, M., Mosqueda, M., Zhong, J., Shankaracharya Unger, M., Stallworth, K., Cameron, D., Rotunno, M. S., Dawes, P., Fowler‐Magaw, M., Keagle, P. J., McDonough, J. A., Boopathy, S., Sena‐Esteves, M., Nickerson, J. A., Lutz, C., Skarnes, W. C., … Bosco, D. A. (2024). Expression of ALS‐PFN1 impairs vesicular degradation in iPSC‐derived microglia. Nature Communications, 15, 2497.

[6] Funes, S., Jung, J., Gadd, D. H., Mosqueda, M., Mosqueda, M., Zhong, J., Shankaracharya Unger, M., Stallworth, K., Cameron, D., Rotunno, M. S., Dawes, P., Fowler‐Magaw, M., Keagle, P. J., McDonough, J. A., Boopathy, S., Sena‐Esteves, M., Nickerson, J. A., Lutz, C., Skarnes, W. C., … Bosco, D. A. (2024). Expression of ALS‐PFN1 impairs vesicular degradation in iPSC‐derived microglia. Nature Communications, 15, 2497.

[7] Giacomelli, E., Vahsen, B. F., Calder, E. L., Xu, Y., Scaber, J., Gray, E., Dafinca, R., Talbot, K., & Studer, L. (2022). Human stem cell models of neurodegeneration: From basic science of amyotrophic lateral sclerosis to clinical translation. Cell Stem Cell, 29, 11–35.

[8] Giacomelli, E., Vahsen, B. F., Calder, E. L., Xu, Y., Scaber, J., Gray, E., Dafinca, R., Talbot, K., & Studer, L. (2022). Human stem cell models of neurodegeneration: From basic science of amyotrophic lateral sclerosis to clinical translation. Cell Stem Cell, 29, 11–35.

[9] Vahsen, B. F., Nalluru, S., Morgan, G. R., Farrimond, L., Carroll, E., Xu, Y., Cramb, K. M. L., Amein, B., Scaber, J., Katsikoudi, A., Candalija, A., Carcolé, M., Dafinca, R., Isaacs, A. M., Wade‐Martins, R., Gray, E., Turner, M. R., Cowley, S. A., & Talbot, K. (2023). C9orf72‐ALS human iPSC microglia are pro‐inflammatory and toxic to co‐cultured motor neurons via MMP9. Nature Communications, 14, 5898.

[10] Vahsen, B. F., Nalluru, S., Morgan, G. R., Farrimond, L., Carroll, E., Xu, Y., Cramb, K. M. L., Amein, B., Scaber, J., Katsikoudi, A., Candalija, A., Carcolé, M., Dafinca, R., Isaacs, A. M., Wade‐Martins, R., Gray, E., Turner, M. R., Cowley, S. A., & Talbot, K. (2023). C9orf72‐ALS human iPSC microglia are pro‐inflammatory and toxic to co‐cultured motor neurons via MMP9. Nature Communications, 14, 5898.

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Recent insights from human induced pluripotent stem cell models into the role of microglia in amyotrophic lateral sclerosis

Affiliations

Recent insights from human induced pluripotent stem cell models into the role of microglia in amyotrophic lateral sclerosis

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