Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response
Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response
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DOI：
10.1096/fj.06-6769com
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发表时间：
2007-05-01
期刊：
影响因子：
4.8
通讯作者：
Murry, Charles E.
中科院分区：
文献类型：
--
作者：
Nussbaum, Jeannette;Minami, Elina;Murry, Charles E.
胚胎干细胞（ES细胞）有希望用于心脏修复，但将其定向分化为心肌细胞仍然具有挑战性。我们研究了心脏是否在体内引导ES细胞向心肌细胞分化，以及同种异体ES细胞是否具有免疫耐受性。未分化的小鼠ES细胞在裸小鼠或免疫活性的同基因小鼠中持续形成心脏畸胎瘤。心脏畸胎瘤的心肌细胞并不比后肢畸胎瘤多，提示缺乏引导分化。胚胎干细胞也在梗死心脏中形成畸胎瘤，表明损伤相关信号并不指导心脏分化。同种异体ES细胞也引起心脏畸胎瘤，但这些在几周后被免疫排斥，与炎症增加和I类和II类组织相容性抗原的上调有关。ES细胞与心肌细胞融合在体内也有发生，但很少。荧光被鉴定为可能被误认为增强的GFP表达和真正的再生的伪影。因此，未分化的ES细胞在正常或梗死心脏中不被引导向心肌细胞的命运，并且没有证据表明ES细胞衍生物的同种异体免疫耐受。涉及ES细胞的成功心脏修复策略将需要控制心脏分化，避免引入未分化的细胞，并且可能需要免疫调节以避免排斥。
Embryonic stem (ES) cells are promising for cardiac repair, but directing their differentiation toward cardiomyocytes remains challenging. We investigated whether the heart guides ES cells toward cardiomyocytes in vivo and whether allogeneic ES cells were immunologically tolerated. Undifferentiated mouse ES cells consistently formed cardiac teratomas in nude or immunocompetent syngeneic mice. Cardiac teratomas contained no more cardiomyocytes than hind-limb teratomas, suggesting lack of guided differentiation. ES cells also formed teratomas in infarcted hearts, indicating injury-related signals did not direct cardiac differentiation. Allogeneic ES cells also caused cardiac teratomas, but these were immunologically rejected after several weeks, in association with increased inflammation and up-regulation of class I and II histocompatibility antigens. Fusion between ES cells and cardiomyocytes occurred in vivo, but was rare. Infarct autofluorescence was identified as an artifact that might be mistaken for enhanced GFP expression and true regeneration. Hence, undifferentiated ES cells were not guided toward a cardiomyocyte fate in either normal or infarcted hearts, and there was no evidence for allogeneic immune tolerance of ES cell derivatives. Successful cardiac repair strategies involving ES cells will need to control cardiac differentiation, avoid introducing undifferentiated cells, and will likely require immune modulation to avoid rejection.