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Immunosuppressive Functions of M2 Macrophages Derived from iPSCs of ALS Patients

35 Pages Posted: 10 Apr 2020 Sneak Peek Status: Review Complete

See all articles by Weihua Zhao

Weihua Zhao

Houston Methodist Research Institute - Department of Neurology

David R. Beers

Houston Methodist Research Institute - Department of Neurology

Jason R. Thonhoff

Houston Methodist Research Institute - Department of Neurology

Aaron D. Thome

Houston Methodist Research Institute - Department of Neurology

Alireza Faridar

Houston Methodist Research Institute - Department of Neurology

Jinghong Wang

Houston Methodist Research Institute - Department of Neurology

Shixiang Wen

Houston Methodist Research Institute - Department of Neurology

Loren Ornelas

Cedars Sinai Medical Center - Board of Governors Regenerative Medicine Institute

Dhruv Sareen

Cedars Sinai Medical Center - Board of Governors Regenerative Medicine Institute; Cedars-Sinai Medical Center, The Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences; University of California, Los Angeles (UCLA) - David Geffen School of Medicine; Cedars Sinai Medical Center - Induced Pluripotent Stem Cell (iPSC) Core (David and Janet Polak Foundation Stem Cell Core Laboratory)

Helen S. Goodridge

Cedars Sinai Medical Center - Board of Governors Regenerative Medicine Institute

Clive N. Svendsen

Cedars Sinai Medical Center - Board of Governors Regenerative Medicine Institute

Stanley H. Appel

Houston Methodist Research Institute - Department of Neurology

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Abstract

Amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease, is a systemic inflammatory disorder that augments disease burden and rates of disease progression, and is pathologically characterized by activated leukocytes. Activated macrophages are members of this family and can be simplistically separated into M1 and M2 cells. M2 macrophages (M2) have been shown to provide therapeutic benefits in mouse models of diabetes and Adriamycin nephrosis by suppressing the pro-inflammatory state. However, the suppressive functions of M2 have not been investigated in ALS, nor have M2 derived from human iPSCs (Induced Pluripotent Stem Cells) been studied for their immunosuppressive potential. In this study, human iPSCs from ALS patients with C9orf72 (C9) mutation or from sporadic ALS patients were differentiated into M2 macrophages, which suppressed activation of pro-inflammatory M1 macrophages as-well-as proliferation of pro-inflammatory CD4+CD25- T lymphocytes (Teffs) of ALS patients. These M2 macrophages also converted ALS Teffs into CD4+CD25+Foxp3+ regulatory T cells (Tregs), and rescued ALS patients’ Tregs from the loss of functional markers CD25 and Foxp3. Furthermore, the ALS Tregs induced or rescued by iPSC-derived M2 cells had strong suppressive functions. Without influence of C9 mutation or disease insult, immunomodulatory effects of ALS iPSC-derived M2 cells behaved similarly to control iPSC-derived M2 cells. This study demonstrates that M2 cells differentiated from ALS patients’ iPSCs have immunosuppressive functions and boost ALS Tregs, and may serve as a candidate for immune-cell-based therapy to mitigate the systemic inflammation occurring in patients with ALS.

Keywords: ALS, M2 macrophages, immunosuppression, induced pluripotent stem cells (iPSC)

Suggested Citation

Zhao, Weihua and Beers, David R. and Thonhoff, Jason R. and Thome, Aaron D. and Faridar, Alireza and Wang, Jinghong and Wen, Shixiang and Ornelas, Loren and Sareen, Dhruv and Goodridge, Helen S. and Svendsen, Clive N. and Appel, Stanley H., Immunosuppressive Functions of M2 Macrophages Derived from iPSCs of ALS Patients. Available at SSRN: https://ssrn.com/abstract=3565028 or http://dx.doi.org/10.2139/ssrn.3565028
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Weihua Zhao

Houston Methodist Research Institute - Department of Neurology

United States

David R. Beers

Houston Methodist Research Institute - Department of Neurology

United States

Jason R. Thonhoff

Houston Methodist Research Institute - Department of Neurology

United States

Aaron D. Thome

Houston Methodist Research Institute - Department of Neurology

United States

Alireza Faridar

Houston Methodist Research Institute - Department of Neurology

United States

Jinghong Wang

Houston Methodist Research Institute - Department of Neurology

United States

Shixiang Wen

Houston Methodist Research Institute - Department of Neurology

United States

Loren Ornelas

Cedars Sinai Medical Center - Board of Governors Regenerative Medicine Institute

8700 Beverly Blvd.
Los Angeles, CA
United States

Dhruv Sareen

Cedars Sinai Medical Center - Board of Governors Regenerative Medicine Institute ( email )

8700 Beverly Blvd.
Los Angeles, CA
United States

Cedars-Sinai Medical Center, The Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences ( email )

8700 Beverly Blvd.
Los Angeles, CA
United States

University of California, Los Angeles (UCLA) - David Geffen School of Medicine ( email )

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

Cedars Sinai Medical Center - Induced Pluripotent Stem Cell (iPSC) Core (David and Janet Polak Foundation Stem Cell Core Laboratory) ( email )

8700 Beverly Blvd.
Advanced Health Sciences Pavilion, Suite A8500
Los Angeles, CA 90048
United States

Helen S. Goodridge

Cedars Sinai Medical Center - Board of Governors Regenerative Medicine Institute

8700 Beverly Blvd.
Los Angeles, CA
United States

Clive N. Svendsen

Cedars Sinai Medical Center - Board of Governors Regenerative Medicine Institute

8700 Beverly Blvd.
Los Angeles, CA
United States

Stanley H. Appel (Contact Author)

Houston Methodist Research Institute - Department of Neurology ( email )

United States

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