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

doi:10.1016/j.isci.2020.101192

Immunosuppressive Functions of M2 Macrophages Derived from iPSCs of Patients with ALS and Healthy Controls

iScience. 2020 Jun 26;23(6):101192. doi: 10.1016/j.isci.2020.101192. Epub 2020 May 23.

Affiliations

¹ Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, 6560 Fannin Street, Suite ST-802, Houston, TX 77030, USA.
² Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Cedars-Sinai Biomanufacturing Center, West Hollywood, CA 90069, USA.
³ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁴ Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, 6560 Fannin Street, Suite ST-802, Houston, TX 77030, USA. Electronic address: sappel@houstonmethodist.org.

Abstract

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.

Keywords: Cellular Neuroscience; Immunology.