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Fate of undifferentiated mouse embryonic stem cells within the rat heart: role of myocardial infarction and immune suppression.

He Q, Trindade PT, Stumm M, Li J, Zammaretti P, Bettiol E, Dubois-Dauphin M, Herrmann F, Kalangos A, Morel D, Jaconi ME - J. Cell. Mol. Med. (2008)

Bottom Line: We found that mESC survival depended on immunosuppression both in normal and infarcted hearts.However, upon Cyclosporin A treatment, both normal and infarcted rat hearts failed to induce selective cardiac differentiation of implanted mESC.Instead, teratomas developed in normal and infarcted rat hearts 1 week and 4 weeks (50% and 100%, respectively) after cell injection.

View Article: PubMed Central - PubMed

Affiliation: Department of Rehabilitation and Geriatrics, Laboratory of Biology of Aging, Geneva University Hospitals, Geneva, Switzerland.

ABSTRACT
Abstract It has recently been suggested that the infarcted rat heart microenvironment could direct pluripotent mouse embryonic stem cells to differentiate into cardiomyocytes through an in situ paracrine action. To investigate whether the heart can function as a cardiogenic niche and confer an immune privilege to embryonic stem cells, we assessed the cardiac differentiation potential of undifferentiated mouse embryonic stem cells (mESC) injected into normal, acutely or chronically infarcted rat hearts. We found that mESC survival depended on immunosuppression both in normal and infarcted hearts. However, upon Cyclosporin A treatment, both normal and infarcted rat hearts failed to induce selective cardiac differentiation of implanted mESC. Instead, teratomas developed in normal and infarcted rat hearts 1 week and 4 weeks (50% and 100%, respectively) after cell injection. Tight control of ESC commitment into a specific cardiac lineage is mandatory to avoid the risk of uncontrolled growth and tumourigenesis following transplantation of highly plastic cells into a diseased myocardium.

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Fate of undifferentiated mouse ESC transplanted into a normal rat heart as a function of time and immune suppression treatment. (A–C) Haematoxylin and eosin (H & E) staining and (D) hBcl2 immunohistochemistry of heart sections 1 week and 4 weeks after cell transplantation in the absence of CsA. Magnification: A, C, D =×10; B =×50. (E, G) Haematoxylin and eosin staining and (F, H) hBcl2 immunohistochemistry of heart sections at 1 and 4 weeks after engraftment in the presence of CsA treatment. Teratomas are visible at 1 (E) and 4 weeks (G, H) under CsA treatment. Magnification: E, G, H =×10; F =×50. I = time of injection.
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fig02: Fate of undifferentiated mouse ESC transplanted into a normal rat heart as a function of time and immune suppression treatment. (A–C) Haematoxylin and eosin (H & E) staining and (D) hBcl2 immunohistochemistry of heart sections 1 week and 4 weeks after cell transplantation in the absence of CsA. Magnification: A, C, D =×10; B =×50. (E, G) Haematoxylin and eosin staining and (F, H) hBcl2 immunohistochemistry of heart sections at 1 and 4 weeks after engraftment in the presence of CsA treatment. Teratomas are visible at 1 (E) and 4 weeks (G, H) under CsA treatment. Magnification: E, G, H =×10; F =×50. I = time of injection.

Mentions: We first tested whether mESC could engraft and survive in a healthy rat myocardium in the absence of immune suppression. We histologically examined hearts either 1 or 4 weeks after transplantation of undifferentiated eGFP-CD63 or hBcl2-positive mESC (Fig. 2, n= 5 and n= 8, respectively). Healthy heart sections stained with haematoxylin and eosin revealed the presence of granulation tissue (Fig. 2A and B) 1 week after engraftment (also containing MHC-II-positive cells, not shown), whereas this was no longer observed 4 weeks after implantation (Fig. 2C and D). At both time-points, no marker-positive mESC were identified at the site of injection, as illustrated by the absence of hBcl2 (0/13, Fig. 2D) or eGFP staining (not shown).


Fate of undifferentiated mouse embryonic stem cells within the rat heart: role of myocardial infarction and immune suppression.

He Q, Trindade PT, Stumm M, Li J, Zammaretti P, Bettiol E, Dubois-Dauphin M, Herrmann F, Kalangos A, Morel D, Jaconi ME - J. Cell. Mol. Med. (2008)

Fate of undifferentiated mouse ESC transplanted into a normal rat heart as a function of time and immune suppression treatment. (A–C) Haematoxylin and eosin (H & E) staining and (D) hBcl2 immunohistochemistry of heart sections 1 week and 4 weeks after cell transplantation in the absence of CsA. Magnification: A, C, D =×10; B =×50. (E, G) Haematoxylin and eosin staining and (F, H) hBcl2 immunohistochemistry of heart sections at 1 and 4 weeks after engraftment in the presence of CsA treatment. Teratomas are visible at 1 (E) and 4 weeks (G, H) under CsA treatment. Magnification: E, G, H =×10; F =×50. I = time of injection.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3823046&req=5

fig02: Fate of undifferentiated mouse ESC transplanted into a normal rat heart as a function of time and immune suppression treatment. (A–C) Haematoxylin and eosin (H & E) staining and (D) hBcl2 immunohistochemistry of heart sections 1 week and 4 weeks after cell transplantation in the absence of CsA. Magnification: A, C, D =×10; B =×50. (E, G) Haematoxylin and eosin staining and (F, H) hBcl2 immunohistochemistry of heart sections at 1 and 4 weeks after engraftment in the presence of CsA treatment. Teratomas are visible at 1 (E) and 4 weeks (G, H) under CsA treatment. Magnification: E, G, H =×10; F =×50. I = time of injection.
Mentions: We first tested whether mESC could engraft and survive in a healthy rat myocardium in the absence of immune suppression. We histologically examined hearts either 1 or 4 weeks after transplantation of undifferentiated eGFP-CD63 or hBcl2-positive mESC (Fig. 2, n= 5 and n= 8, respectively). Healthy heart sections stained with haematoxylin and eosin revealed the presence of granulation tissue (Fig. 2A and B) 1 week after engraftment (also containing MHC-II-positive cells, not shown), whereas this was no longer observed 4 weeks after implantation (Fig. 2C and D). At both time-points, no marker-positive mESC were identified at the site of injection, as illustrated by the absence of hBcl2 (0/13, Fig. 2D) or eGFP staining (not shown).

Bottom Line: We found that mESC survival depended on immunosuppression both in normal and infarcted hearts.However, upon Cyclosporin A treatment, both normal and infarcted rat hearts failed to induce selective cardiac differentiation of implanted mESC.Instead, teratomas developed in normal and infarcted rat hearts 1 week and 4 weeks (50% and 100%, respectively) after cell injection.

View Article: PubMed Central - PubMed

Affiliation: Department of Rehabilitation and Geriatrics, Laboratory of Biology of Aging, Geneva University Hospitals, Geneva, Switzerland.

ABSTRACT
Abstract It has recently been suggested that the infarcted rat heart microenvironment could direct pluripotent mouse embryonic stem cells to differentiate into cardiomyocytes through an in situ paracrine action. To investigate whether the heart can function as a cardiogenic niche and confer an immune privilege to embryonic stem cells, we assessed the cardiac differentiation potential of undifferentiated mouse embryonic stem cells (mESC) injected into normal, acutely or chronically infarcted rat hearts. We found that mESC survival depended on immunosuppression both in normal and infarcted hearts. However, upon Cyclosporin A treatment, both normal and infarcted rat hearts failed to induce selective cardiac differentiation of implanted mESC. Instead, teratomas developed in normal and infarcted rat hearts 1 week and 4 weeks (50% and 100%, respectively) after cell injection. Tight control of ESC commitment into a specific cardiac lineage is mandatory to avoid the risk of uncontrolled growth and tumourigenesis following transplantation of highly plastic cells into a diseased myocardium.

Show MeSH
Related in: MedlinePlus