Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics

Nigel G Kooreman; Patricia E de Almeida; Jonathan P Stack; Raman V Nelakanti; Sebastian Diecke; Ning-Yi Shao; Rutger-Jan Swijnenburg; Veronica Sanchez-Freire; Elena Matsa; Chun Liu; Andrew J Connolly; Jaap F Hamming; Paul H A Quax; Michael A Brehm; Dale L Greiner; Leonard D Shultz; Joseph C Wu

doi:10.1016/j.celrep.2017.08.003

Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics

Cell Rep. 2017 Aug 22;20(8):1978-1990. doi: 10.1016/j.celrep.2017.08.003.

Authors

Nigel G Kooreman¹, Patricia E de Almeida², Jonathan P Stack³, Raman V Nelakanti², Sebastian Diecke², Ning-Yi Shao², Rutger-Jan Swijnenburg⁴, Veronica Sanchez-Freire², Elena Matsa², Chun Liu², Andrew J Connolly⁵, Jaap F Hamming⁴, Paul H A Quax⁴, Michael A Brehm⁶, Dale L Greiner⁷, Leonard D Shultz⁸, Joseph C Wu⁹

Affiliations

¹ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA; Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
² Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA; Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
³ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA; Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California, USA.
⁴ Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
⁵ Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
⁶ Diabetes Center of Excellence, Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
⁷ Diabetes Center of Excellence, Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address: dale.greiner@umassmed.edu.
⁸ The Jackson Laboratory, Bar Harbor, ME, USA. Electronic address: lenny.shultz@jax.org.
⁹ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA; Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA. Electronic address: joewu@stanford.edu.

Abstract

There is growing interest in using embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) derivatives for tissue regeneration. However, an increased understanding of human immune responses to stem cell-derived allografts is necessary for maintaining long-term graft persistence. To model this alloimmunity, humanized mice engrafted with human hematopoietic and immune cells could prove to be useful. In this study, an in-depth analysis of graft-infiltrating human lymphocytes and splenocytes revealed that humanized mice incompletely model human immune responses toward allogeneic stem cells and their derivatives. Furthermore, using an "allogenized" mouse model, we show the feasibility of reconstituting immunodeficient mice with a functional mouse immune system and describe a key role of innate immune cells in the rejection of mouse stem cell allografts.

Keywords: T cell exhaustion; allograft; humanized mice; immunogenicity; pluripotent stem cells; stem cell therapeutics; wasting disease.

MeSH terms

Animals
Disease Models, Animal
Graft Rejection
Hematopoietic Stem Cell Transplantation / methods*
Humans
Immunity, Innate / immunology*
Mice
Pluripotent Stem Cells / metabolism*
Transplantation Conditioning / methods*

Abstract

MeSH terms

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