ACVR1R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages

Koji Matsuo; Abigail Lepinski; Robert D Chavez; Emilie Barruet; Ashley Pereira; Tania A Moody; Amy N Ton; Aditi Sharma; Judith Hellman; Kiichiro Tomoda; Mary C Nakamura; Edward C Hsiao

doi:10.1016/j.bone.2021.116129

ACVR1^R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages

Bone. 2021 Dec:153:116129. doi: 10.1016/j.bone.2021.116129. Epub 2021 Jul 24.

Authors

Affiliations

¹ Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA, USA; The Institute for Human Genetics, University of California, San Francisco, CA, USA; The Program in Craniofacial Biology, University of California, San Francisco, CA, USA.
² Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA, USA; The Institute for Human Genetics, University of California, San Francisco, CA, USA; The Program in Craniofacial Biology, University of California, San Francisco, CA, USA; Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, MA, USA.
³ Department of Anesthesia and Perioperative Care, University of California, San Francisco, USA.
⁴ Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.
⁵ Medical Service, San Francisco Veterans Affairs Healthcare System, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA.
⁶ Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA, USA; The Institute for Human Genetics, University of California, San Francisco, CA, USA; The Program in Craniofacial Biology, University of California, San Francisco, CA, USA. Electronic address: Edward.hsiao@ucsf.edu.

Abstract

Macrophages play crucial roles in many human disease processes. However, obtaining large numbers of primary cells for study is often difficult. We describe 2D and 3D methods for directing human induced pluripotent stem cells (hiPSCs) into macrophages (iMACs). iMACs generated in 2D culture showed functional similarities to human primary monocyte-derived M2-like macrophages, and could be successfully polarized into a M1-like phenotype. Both M1- and M2-like iMACs showed phagocytic activity and reactivity to endogenous or exogenous stimuli. In contrast, iMACs generated by a 3D culture system showed mixed M1- and M2-like functional characteristics. 2D-iMACs from patients with fibrodysplasia ossificans progressiva (FOP), an inherited disease with progressive heterotopic ossification driven by inflammation, showed prolonged inflammatory cytokine production and higher Activin A production after M1-like polarization, resulting in dampened responses to additional LPS stimulation. These results demonstrate a simple and robust way of creating hiPSC-derived M1- and M2-like macrophage lineages, while identifying macrophages as a source of Activin A that may drive heterotopic ossification in FOP.

Keywords: Activin A; Cytokines; FOP; Fibrodysplasia ossificans progressiva; Heterotopic ossification; Human induced pluripotent stem cells; Immune activation; Inflammation; Macrophages.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Activin Receptors, Type I / genetics
Activin Receptors, Type I / metabolism
Humans
Induced Pluripotent Stem Cells* / metabolism
Macrophages / metabolism
Myositis Ossificans*
Ossification, Heterotopic*
Signal Transduction

Substances

ACVR1 protein, human
Activin Receptors, Type I

Abstract

Publication types

MeSH terms

Substances

Grants and funding