Safety and efficacy of embryonic stem cell microenvironment in a leukemia mouse model.

The embryonic stem cell (ESC) microenvironment can promote the proliferation of terminal cells and reduce the invasiveness of tumor cells. However, implanting ESCs directly in vivo can result in tumorigenicity, immune rejection after differentiation, and graft-versus-host reaction. Therefore, safety is very important in the clinical application of ESCs. We injected ESCs modified with a suicide gene into a leukemia mouse model through peripheral blood to observe the treatment effectiveness. In addition, according to the pre-test, we set the time point of differentiation after transplantation and then activated the suicide gene to kill the ESCs that we had initially implanted, hoping to avoid the risks mentioned earlier. Our results indicated that the body weight and survival rates of mice treated with an ESC microenvironment increased, and leukemic cells in peripheral blood and bone marrow decreased compared with untreated mice. There was no obvious teratoma in mice that received ESC therapy and induced the suicide gene at the proper time during the observation period, while an apparent teratoma was observed in the lungs of mice which received ESC therapy and never induced the suicide gene. Therefore, the ESC microenvironment can promote self-healing of the in vivo microenvironment. Inducing the suicide gene at the appropriate time can reduce or even avoid tumorigenicity and immune rejection after transplantation of ESCs in vivo and improve the safety of their clinical application.

[1]  Y. Liu,et al.  ES Micro-Environment Enhances Stemness and Inhibits Apoptosis in Human Limbal Stem Cells via the Maintenance of Telomerase Activity , 2013, PloS one.

[2]  B. Lahn,et al.  Protecting against wayward human induced pluripotent stem cells with a suicide gene. , 2012, Biomaterials.

[3]  N. Zavazava,et al.  Embryonic Stem Cell‐Derived T Cells Induce Lethal Graft‐Versus‐Host Disease and Reject Allogenic Skin Grafts upon Thymic Selection , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  Yong-Yeon Cho,et al.  Embryonic stem‐cell‐preconditioned microenvironment induces loss of cancer cell properties in human melanoma cells , 2011, Pigment cell & melanoma research.

[5]  Fen Chen,et al.  Enhanced functional properties of corneal epithelial cells by coculture with embryonic stem cells via the integrin β1-FAK-PI3K/Akt pathway. , 2011, The international journal of biochemistry & cell biology.

[6]  S. Lim,et al.  Human embryonic stem cell-derived mesenchymal stem cells as cellular delivery vehicles for prodrug gene therapy of glioblastoma. , 2011, Human gene therapy.

[7]  Y. Liu,et al.  Enhancement of long-term proliferative capacity of rabbit corneal epithelial cells by embryonic stem cell conditioned medium. , 2010, Tissue engineering. Part C, Methods.

[8]  T. Ekström,et al.  Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy. , 2010, Neuro-oncology.

[9]  Y. Liu,et al.  Enhanced survival in vitro of human corneal endothelial cells using mouse embryonic stem cell conditioned medium , 2010, Molecular vision.

[10]  Jingjun Jin,et al.  Generation of Thymic Epithelial Cell Progenitors by Mouse Embryonic Stem Cells , 2009, Stem cells.

[11]  N. de Wind,et al.  Abrogation of microsatellite-instable tumors using a highly selective suicide gene/prodrug combination. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[12]  Hung Li,et al.  Induction of GAP‐43 modulates neuroplasticity in PBSC (CD34+) implanted‐Parkinson's model , 2009, Journal of neuroscience research.

[13]  R. Malenka,et al.  Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[14]  W. Paulus,et al.  The Tumorigenicity of Mouse Embryonic Stem Cells and In Vitro Differentiated Neuronal Cells Is Controlled by the Recipients' Immune Response , 2008, PloS one.

[15]  C. Link,et al.  Hematopoietic Mixed Chimerism Derived from Allogeneic Embryonic Stem Cells Prevents Autoimmune Diabetes Mellitus in NOD Mice , 2008, Stem cells.

[16]  R. Crystal,et al.  Ablation of tumor-derived stem cells transplanted to the central nervous system by genetic modification of embryonic stem cells with a suicide gene. , 2007, Human gene therapy.

[17]  J. Odorico,et al.  Undifferentiated murine embryonic stem cells cannot induce portal tolerance but may possess immune privilege secondary to reduced major histocompatibility complex antigen expression. , 2006, Stem cells and development.

[18]  N. Zavazava,et al.  Immunogenicity and Engraftment of Mouse Embryonic Stem Cells in Allogeneic Recipients , 2006, Stem cells.

[19]  M. Hendrix,et al.  A Three‐Dimensional Model to Study the Epigenetic Effects Induced by the Microenvironment of Human Embryonic Stem Cells , 2006, Stem cells.

[20]  Sanjiv S. Gambhir,et al.  In Vivo Visualization of Embryonic Stem Cell Survival, Proliferation, and Migration After Cardiac Delivery , 2006, Circulation.

[21]  Weiqiang Li,et al.  Establishment and Characteristics of Hybrid Embryonic Stem Cell Lines from Blastocysts of the (C57BL/6J×129/J) F1 Mouse , 2006 .

[22]  J. Jones,et al.  Therapeutic potential of stem cells in diabetes. , 2006, Handbook of experimental pharmacology.

[23]  I. Weissman,et al.  They are not stealthy in the heart: embryonic stem cells trigger cell infiltration, humoral and T-lymphocyte-based host immune response. , 2005, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[24]  W. Paulus,et al.  Fate of pre-differentiated mouse embryonic stem cells transplanted in unilaterally 6-hydroxydopamine lesioned rats: Histological characterization of the grafted cells , 2005, Brain Research.

[25]  N. Zavazava,et al.  Induction of Stable Mixed Chimerism by Embryonic Stem Cells Requires Functional Fas/FasL Engagement , 2005, Transplantation.

[26]  Linzhao Cheng,et al.  Functional antigen-presenting leucocytes derived from human embryonic stem cells in vitro , 2004, The Lancet.

[27]  Thomas M. Schmitt,et al.  Induction of T cell development and establishment of T cell competence from embryonic stem cells differentiated in vitro , 2004, Nature Immunology.

[28]  R. Burt,et al.  Embryonic Stem Cells As an Alternate Marrow Donor Source: Engraftment without Graft-Versus-Host Disease , 2004 .

[29]  宮城 司.  Flk1[+] cells derived from mouse embryonic stem cells reconstitute hematopoiesis in vivo in SCID mice , 2003 .

[30]  Bruce G. Jenkins,et al.  Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[31]  H. Deeg,et al.  Stem cell transplantation: supportive care and long-term complications. , 2002, Hematology. American Society of Hematology. Education Program.

[32]  R. Ilaria,et al.  Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571. , 2001, Blood.

[33]  J. Dick,et al.  High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase. , 1998, Blood.