Derived myeloid lineage induced pluripotent stem as a platform to study human C-C chemokine receptor type 5Δ32 homozygotes

Guibin Chen; Francesca Calcaterra; Yuchi Ma; Xianfeng Ping; Elena Pontarini; Dan Yang; Ferdinando Oriolo; Zhen Yu; Assunta Cancellara; Joanna Mikulak; Yuting Huang; Silvia Della Bella; Yangtengyu Liu; Leslie G Biesecker; Rebecca L Harper; Clifton L Dalgard; Manfred Boehm; Domenico Mavilio

doi:10.1016/j.isci.2023.108331

Derived myeloid lineage induced pluripotent stem as a platform to study human C-C chemokine receptor type 5Δ32 homozygotes

iScience. 2023 Oct 28;26(11):108331. doi: 10.1016/j.isci.2023.108331. eCollection 2023 Nov 17.

Authors

Guibin Chen¹, Francesca Calcaterra^{2

3}, Yuchi Ma¹, Xianfeng Ping^{1

4}, Elena Pontarini^{2

5}, Dan Yang¹, Ferdinando Oriolo^{2

3}, Zhen Yu¹, Assunta Cancellara^{2

3}, Joanna Mikulak², Yuting Huang¹, Silvia Della Bella^{2

3}, Yangtengyu Liu⁶, Leslie G Biesecker⁷, Rebecca L Harper¹, Clifton L Dalgard⁸, Manfred Boehm¹, Domenico Mavilio^{2

3}

Affiliations

¹ Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
² Unit of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy.
³ Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, 20054 Segrate, Italy.
⁴ Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China.
⁵ Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK.
⁶ Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, China.
⁷ Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ The American Genome Center, Uniformed Services University, Bethesda, MD, USA.

Abstract

The C-C chemokine receptor type 5 (CCR5) expressed on immune cells supports inflammatory responses by directing cells to the inflammation site. CCR5 is also a major coreceptor for macrophage tropic human immunodeficiency viruses (R5-HIV-1) and its variants can confer protection from HIV infection, making it an ideal candidate to target for therapy. We developed a stepwise protocol that differentiates induced pluripotent stem cells (iPSCs) from individuals homozygous for the CCR5Δ32 variant and healthy volunteers into myeloid lineage induced monocytes (iMono) and macrophages (iMac). By characterizing iMono and iMac against their primary counterparts, we demonstrated that CCR5Δ32 homozygous cells are endowed with similar pluripotent potential for self-renewal and differentiation as iPSC lines generated from non-variant individuals while also showing resistance to HIV infection. In conclusion, these cells are a platform to investigate CCR5 pathophysiology in HIV-positive and negative individuals and to help develop novel therapies.

Keywords: Immunology; Molecular biology; Stem cells research.

Abstract

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