Immunosuppressive Functions of M2 Macrophages Derived from iPSCs of Patients with ALS and Healthy Controls
Weihua Zhao,
David R. Beers,
Jason R. Thonhoff,
Aaron D. Thome,
Alireza Faridar,
Jinghong Wang,
Shixiang Wen,
Loren Ornelas,
Dhruv Sareen,
Helen S. Goodridge,
Clive N. Svendsen,
Stanley H. Appel
Affiliations
Weihua Zhao
Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, 6560 Fannin Street, Suite ST-802, Houston, TX 77030, USA
David R. Beers
Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, 6560 Fannin Street, Suite ST-802, Houston, TX 77030, USA
Jason R. Thonhoff
Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, 6560 Fannin Street, Suite ST-802, Houston, TX 77030, USA
Aaron D. Thome
Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, 6560 Fannin Street, Suite ST-802, Houston, TX 77030, USA
Alireza Faridar
Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, 6560 Fannin Street, Suite ST-802, Houston, TX 77030, USA
Jinghong Wang
Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, 6560 Fannin Street, Suite ST-802, Houston, TX 77030, USA
Shixiang Wen
Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, 6560 Fannin Street, Suite ST-802, Houston, TX 77030, USA
Loren Ornelas
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Cedars-Sinai Biomanufacturing Center, West Hollywood, CA 90069, USA
Dhruv Sareen
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Cedars-Sinai Biomanufacturing Center, West Hollywood, CA 90069, USA
Helen S. Goodridge
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Clive N. Svendsen
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Stanley H. Appel
Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, 6560 Fannin Street, Suite ST-802, Houston, TX 77030, USA; Corresponding author
Summary: Amyotrophic lateral sclerosis (ALS) is a disorder with immune alterations that augment disease severity. M2 macrophages benefit diabetic and nephrotic mice by suppressing the pro-inflammatory state. However, neither have M2 cells been investigated in ALS nor have human induced pluripotent stem cell (iPSC)-derived M2 cells been thoroughly studied for immunosuppressive potentials. Here, iPSCs of C9orf72 mutated or sporadic ALS patients were differentiated into M2 macrophages, which suppressed activation of pro-inflammatory M1 macrophages as well as proliferation of ALS CD4+CD25- Tc (Teffs). M2 cells converted ALS Teffs into CD4+CD25+Foxp3+ regulatory T cells (Tregs) and rescued Tregs of ALS patients from losing CD25 and Foxp3. Furthermore, Tregs induced or rescued by iPSC-derived M2 had strong suppressive functions. ALS iPSC-derived M2 cells including those with C9orf72 mutation had similar immunomodulatory activity as control iPSC-derived M2 cells. This study demonstrates that M2 cells differentiated from iPSCs of ALS patients are immunosuppressive, boost ALS Tregs, and may serve as a candidate for immune-cell-based therapy to mitigate inflammation in ALS.
