Cymerus™ iPSC-MSCs significantly prolong survival in a pre-clinical, humanized mouse model of Graft-vs-host disease

E. Ilker Ozay; Jyothi Vijayaraghavan; Gabriela Gonzalez-Perez; Sudarvili Shanthalingam; Heather L. Sherman; Daniel T. Garrigan, Jr.; Karthik Chandiran; Joe A. Torres; Barbara A. Osborne; Gregory N. Tew; Igor I. Slukvin; Ross A. Macdonald; Kilian Kelly; Lisa M. Minter

Stem Cell Research (Mar 2019)

Cymerus™ iPSC-MSCs significantly prolong survival in a pre-clinical, humanized mouse model of Graft-vs-host disease

E. Ilker Ozay,
Jyothi Vijayaraghavan,
Gabriela Gonzalez-Perez,
Sudarvili Shanthalingam,
Heather L. Sherman,
Daniel T. Garrigan, Jr.,
Karthik Chandiran,
Joe A. Torres,
Barbara A. Osborne,
Gregory N. Tew,
Igor I. Slukvin,
Ross A. Macdonald,
Kilian Kelly,
Lisa M. Minter

Affiliations

E. Ilker Ozay: Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, United States; Department of Veterinary & Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States; Department of Polymer Science & Engineering, University of Massachusetts Amherst, Amherst, MA 01003, United States
Jyothi Vijayaraghavan: Department of Veterinary & Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
Gabriela Gonzalez-Perez: Department of Veterinary & Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
Sudarvili Shanthalingam: Department of Veterinary & Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
Heather L. Sherman: Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, United States; Department of Veterinary & Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
Daniel T. Garrigan, Jr.: Department of Veterinary & Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
Karthik Chandiran: Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, United States; Department of Veterinary & Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
Joe A. Torres: Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, United States; Department of Veterinary & Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
Barbara A. Osborne: Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, United States; Department of Veterinary & Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
Gregory N. Tew: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
Igor I. Slukvin: Cynata Therapeutics Limited, Carlton, Victoria 3053, Australia; Department of Polymer Science & Engineering, University of Massachusetts Amherst, Amherst, MA 01003, United States
Ross A. Macdonald: Department of Polymer Science & Engineering, University of Massachusetts Amherst, Amherst, MA 01003, United States
Kilian Kelly: Department of Polymer Science & Engineering, University of Massachusetts Amherst, Amherst, MA 01003, United States
Lisa M. Minter: Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, United States; Department of Veterinary & Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States; Corresponding author at: Department of Veterinary & Animal Sciences, 427K Integrated Sciences Building, 661 North Pleasant Street, University of Massachusetts Amherst, Amherst, MA 01003, United States.

Journal volume & issue: Vol. 35

Abstract

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The immune-mediated tissue destruction of graft-vs-host disease (GvHD) remains a major barrier to greater use of hematopoietic stem cell transplantation (HSCT). Mesenchymal stem cells (MSCs) have intrinsic immunosuppressive qualities and are being actively investigated as a therapeutic strategy for treating GvHD. We characterized Cymerus™ MSCs, which are derived from adult, induced pluripotent stem cells (iPSCs), and show they display surface markers and tri-lineage differentiation consistent with MSCs isolated from bone marrow (BM). Administering iPSC-MSCs altered phosphorylation and cellular localization of the T cell-specific kinase, Protein Kinase C theta (PKCθ), attenuated disease severity, and prolonged survival in a humanized mouse model of GvHD. Finally, we evaluated a constellation of pro-inflammatory molecules on circulating PBMCs that correlated closely with disease progression and which may serve as biomarkers to monitor therapeutic response. Altogether, our data suggest Cymerus iPSC-MSCs offer the potential for an off-the-shelf, cell-based therapy to treat GvHD. Keywords: PKCθ, Graft-vs-host disease, Mesenchymal stem cell, Induced pluripotent stem cell, Humanized mouse model

Published in Stem Cell Research

ISSN: 1873-5061 (Print); 1876-7753 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: https://www.journals.elsevier.com/stem-cell-research

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