Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics

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

doi:10.1016/j.celrep.2017.08.003

Abstract

SummaryThere 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.

Highlights

Human Immune-Engrafted NOD.Cg-Prkdcscid IL2rgtm1Wj1/Sz (NSG) Mice Are Unable to Completely Reject Allogeneic human embryonic stem cells (hESCs) We used both the hSRC (NSG mice engrafted with human leukocyte antigen (HLA)-A2neg hematopoietic stem cells (HSCs)) and hBLT (NSG mice engrafted with HLA-A2neg HSCs and fetal tissue) to model the allogeneic human immune responses to HLA-mismatched (HLA-A2pos) hESCs
The hESC survival in these mice, as well as in control non-engrafted NSG and immunocompetent C57BL/6 mice, was longitudinally monitored in vivo using bioluminescence imaging (BLI). Both the hSRC and non-engrafted NSG mice were unable to completely reject allogeneic hESCs implanted at either injection site, whereas the immunocompetent C57BL/6 mice completely rejected the hESC grafts within 2 weeks (Figures S1A, S1C, S1D, and S1F)
To investigate whether low expression of major histocompatibility complex class I (MHC class I) in hESCs played a role in the failure of hSRC mice to reject these cells, hESCs were treated with interferon gamma (IFN-g) for 24 hr prior to implantation into hSRC mice to increase expression of MHC class I and cell immunogenicity (Drukker et al, 2002)

Summary

Introduction

Since the first isolation of human embryonic stem cells (hESCs) (Thomson et al, 1998) and creation of induced pluripotent stem cells (iPSCs) (Takahashi et al, 2007; Takahashi and Yamanaka, 2006), the field of regenerative medicine has been investigating the therapeutic potential of these cells for cardiac diseases (Nguyen et al, 2016), neurological diseases (Barberi et al, 2003), hepatic failure (Soto-Gutierrez et al, 2006), diabetes (Pagliuca et al, 2014), and macular degeneration (Homma et al, 2013). Advances have been made in tolerizing mice to accept human ESC- and iPSCderived progenitor grafts for long-term monitoring of graft behavior (Lui et al, 2014). To date, it is still not clear how the human immune system would respond to allogeneic human ESC or iPSC grafts. This question would need to be answered before pluripotent stem cell (PSC) therapy, including both ESCs and iPSCs, could be widely implemented in clinical practice

Methods

Results

Discussion

Conclusion