They are not stealthy in the heart: embryonic stem cells trigger cell infiltration, humoral and T-lymphocyte-based host immune response☆

Kofidis, Theo; deBruin, Jorg Lucas; Tanaka, Masashi; Zwierzchoniewska, Monika; Weissman, Irving L.; Fedoseyeva, Eugenia V.; Haverich, Axel; Robbins, Robert C.

doi:10.1016/j.ejcts.2005.03.049

Cited by 89 publications

(64 citation statements)

References 25 publications

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“…In vitro studies with human ES cells also demonstrated that cytotoxic immune responses by T cells were exclusively induced following IFNγ stimulation and that natural killer (NK) cell response was negligible [23,24]. In some studies mouse ES cells exhibited a strong humoral and cellular immune response after in vivo application into injured myocardium in allogeneic settings [4,5]. In contrast, Bonde et al [3] described the inhibition of allo-responses to donor MHC antigens and the development of a multi-lineage mixed chimerism after in vivo administration of mouse ES cells into sublethally irradiated allogeneic hosts.…”

Section: Discussionmentioning

confidence: 98%

“…There are several reports of a robust immune-privileged ('tolerogenic') state of ESC of mice, humans and rats after engraftment [1][2][3], while others described an increase of immunogenicity following transplantation with proceeding differentiation [4,5]. Expression of structures recognized by the host immune system varies between the species, e.g.…”

Section: Introductionmentioning

confidence: 99%

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Low immunogenicity of endothelial derivatives from rat embryonic stem cell-like cells

et al. 2009

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Embryonic stem cells (ESC) are suggested to be immune-privileged, but they carry the risk of uncontrolled expansion and malignancy. Upon differentiation they lose their tumor-forming capacity, but they become immunogenic by the expression of a normal set of MHC molecules. This immunogenicity might trigger rejection after application in regenerative therapies. In this study MHC expression of and immune responses to endothelial derivatives of rat embryonic stem cell-like cells (RESC) under inflammatory conditions were determined in comparison to primary rat aortic endothelial cells (ECs). Cellular as well as humoral allo-recognition was analyzed in vitro. In addition, immune reactions in vivo were assessed by allo-antibody production and determination of interferon-γ (IFNγ)-secreting allo-reactive T cells. RESC derivatives expressed low but significant levels of MHC class I, and no MHC class II. In response to IFNγ MHC class I expression was enhanced, while class II transactivator induction failed completely in these cells; MHC class II expression remained consistently absent. Functionally, the RESC derivatives showed a reduced allo-stimulatory capacity, protection against humoral allo-recognition in vitro and a slightly diminished susceptibility to cytotoxic T cell lysis. Furthermore, in vivo experiments demonstrated that these cells do not trigger host immune reactions, characterized by no allo-antibody production and no induction of allo-reactive memory T cells. Our results show that endothelial derivatives of RESC have a distinctive reduced immunogenic potency even under inflammatory conditions.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Low immunogenicity of endothelial derivatives from rat embryonic stem cell-like cells

et al. 2009

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“…However, once hESCs, isolated from the ICM of blastocyst stage embryos, could be grown into cell lines, extensive studies showed that the hESC lines expressed very low levels of the MHC-I complex [3] and this increased only after differentiation of hESCs. Thus, the basal level of immunogenicity in hESC lines increases following differentiation [3,4,[25][26][27]; although they are less immunogenic than adult cells [4]. It was unclear whether the low levels of MHC-I in hESCs are related to their unique developmental origin or to their pluripotent phenotype.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming of the MHC‐I and Its Regulation by NFκB in Human‐Induced Pluripotent Stem Cells

et al. 2012

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The immunogenicity of human pluripotent stem cells plays a major role in their potential use in the clinic. We show that, during their reprogramming, human-induced pluripotent stem (iPS) cells downregulate expression of human leukocyte antigen (HLA)-A/B/C and b2 microglobulin (b2M), the two components of major histocompatibility complex-I (MHC-I). MHC-I expression in iPS cells can be restored by differentiation or treatment with interferongamma (IFNc). To analyze the molecular mechanisms that regulate the expression of the MHC-I molecules in human iPS cells, we searched for correlation between the expression of HLA-A/B/C and b2M and the expression of transcription factors that bind to the promoter of these genes. Our results show a significant positive correlation between MHC-I expression and expression of the nuclear factors, nuclear factor kappa B 1 (NFjB1) and RelA, at the levels of RNA, protein and was confirmed by chromatin binding. Concordantly, we detected robust levels of NFjB1 and RelA proteins in the nucleus of somatic cells but not in the iPS cell derived from them. Overexpression of NFjB1 and RelA in undifferentiated pluripotent stem cells led to induction in expression of MHC-I, whereas silencing NFjB1 and RelA by small hairpin RNA decreased the expression of b2M after IFNc treatment. Our data point to the critical role of NFjB proteins in regulating the MHC-I expression in human pluripotent stem cells. STEM

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“…Moreover, studies suggest that grafts could induce arrythmias [Smits et al, 2003;Menasche et al, 2003;Perin et al, 2003] and exacerbate conduction abnormalities in the failing heart [Chen et al, 2006]. Other undesirable consequences of transplantation include immunogenic responses [Kofidis et al, 2005], abnormal tissue architecture [Whittaker et al, 2003], neoplastic predisposition, and accelerated cell death [Muller-Ehmsen et al, 2002].3D cultures of neonatal and adult cardiac myocytes in artificial scaffolds have been engineered to develop functional micro-tissues [Akins et al, 1999;Baar et al, 2004;Kelm et al, 2004] for investigations of the vasculature and perfusion in cultured myocardium [Carrier et al, 2002;Watzka et al, 2004] and for repair of damaged myocardium [Hoerstrup et al, 2000;Yang et al, 2001]. Although the 3D-models containing differentiated cardiomyocytes provide a direct source of contractile tissue to repair damaged myocardium, the development of these systems has been far from adequate.…”

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confidence: 99%

3D‐model of adult cardiac stem cells promotes cardiac differentiation and resistance to oxidative stress

Bartosh

Wang

Rosales

et al. 2008

J of Cellular Biochemistry

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The regenerative inadequacy of the injured myocardium leads to adverse remodeling, cardiac dysfunction, and heart disease. Stem cellreplacement of damaged myocardium faces major challenges such as inappropriate differentiation, cellular uncoupling, scar formation, and accelerated apoptosis of transplanted cells. These challenges can be met by engineering an in vitro system for delivering stem cells capable of cardiac differentiation, tissue integration, and resistance to oxidative stress. In this study, we describe the formation of three-dimensional (3D) cell aggregates (''cardiospheres'') by putative stem cells isolated from adult dog myocardium using poly-L-ornithine. De novo formation of cardiospheres in growth factor-containing medium occurred over a period of 2-3 weeks, but accelerated to 2-3 days when seeded on poly-Lornithine. Older cardiospheres developed foci of ''beating'' cells upon co-culture with rat neonatal cardiomyocytes. Cardiospheres contained cells that exhibited characteristics of undifferentiated cells; differentiating cardiomyocytes with organized contractile machinery; and vascular cells capable of forming ''vessel-like'' networks. They exhibited strong resistance to elevated concentrations of hydrogen peroxide in culture and survived subcutaneous injections without undergoing neoplastic transformation up to 3 weeks post-transplantation. These findings suggest that cardiospheres are potentially useful for delivering functional stem cells to the damaged heart. J. Cell. Biochem. 105: 612-623, 2008. ß 2008 KEY WORDS: CARDIOMYOCYTES; CARDIOSPHERES; DIFFERENTIATION; ENDOTHELIAL CELLS; GROWTH FACTORS; OXIDATIVE STRESS; POLY-L-ORNITHINE; SMOOTH MUSCLE CELLS; SPHEROIDS; STEM CELLS T he progressive loss of cardiomyocytes coupled with the poor regenerative capacity of myocardial tissue following acute ischemia or oxidative stress result in the proliferation of fibroblasts, scarring, decreased cardiac performance, compensatory hypertrophy, and ultimately, lead to heart failure [Claycomb, 1992;Frey and Olson, 2003]. Advances in medicine and technology have led to new strategies in cardiac repair involving transplantation or infusion of neonatal cardiomyocytes [Muller-Ehmsen et al., 2002], skeletal myoblasts [Taylor et al., 1998;Suzuki et al., 2001], embryonic stem cells [Min et al., 2002], endothelial cells and/or progenitors [Condorelli et al., 2001;Murasawa et al., 2005], adult mesenchymal cells [Gojo et al., 2003;Makkar et al., 2005], or bone marrow-derived cells [Orlic et al., 2001;Strauer et al., 2002;Beeres et al., 2006]. Promising results have been obtained in many cases showing improvement in cardiac performance [Kehat et al., 2004], however, studies demonstrating development of a fully functional syncytium between the grafted cells and the recipient myocardium are limited and short-term. Grafted cells often exhibit abnormal action Journal of Cellular Biochemistry 105:612-623 (2008) Journal of Cellular Biochemistry ARTICLE 612Abbreviations used: 3D, three-dimensional; FGF-2, fibro...

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They are not stealthy in the heart: embryonic stem cells trigger cell infiltration, humoral and T-lymphocyte-based host immune response☆

Abstract: An immune response against transplanted ESC was demonstrated and the future use of ESC will likely require the use of systemic immunosuppression.

Cited by 89 publications

References 25 publications

Low immunogenicity of endothelial derivatives from rat embryonic stem cell-like cells

Low immunogenicity of endothelial derivatives from rat embryonic stem cell-like cells

Reprogramming of the MHC‐I and Its Regulation by NFκB in Human‐Induced Pluripotent Stem Cells

3D‐model of adult cardiac stem cells promotes cardiac differentiation and resistance to oxidative stress

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