Teratoma Formation Leads to Failure of Treatment for Type I Diabetes Using Embryonic Stem Cell-Derived Insulin-Producing Cells

Fujikawa, Takahisa; Oh, Seh–Hoon; Pi, Liya; Hatch, Heather; Shupe, Tom; Petersen, Bryon E.

doi:10.1016/s0002-9440(10)62488-1

Cited by 292 publications

(195 citation statements)

References 37 publications

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“…Teratoma formation was reported when mouse embryonic stem cell (mESC)-derived insulin producing islets [Fujikawa et al, 2005], mESC-derived cardiomyocytes [Cao et al, 2006], and mESC-derived neurons [Schuldiner et al, 2001] were transplanted into immunosuppressed mice even though there was successful engraftment and functional improvement. When undifferentiated hESCs were injected into the hind limb muscles or under the kidney capsule of SCID mice, teratomas were readily formed after 8-12 weeks [Richards et al, 2002] but injection of hESC-derived neurons into the brain of immunosuppressed fetal mice did not result in the formation of any teratomas after 8 weeks [Yang et al, 2008].…”

Section: Immunorejectionmentioning

confidence: 99%

Taking stem cells to the clinic: Major challenges

Bongso

Fong

Gauthaman

2008

J of Cellular Biochemistry

167

111

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Stem cell therapy offers tremendous promise in the treatment of many incurable diseases. A variety of stem cell types are being studied but human embryonic stem cells (hESCs) appear to be the most versatile as they are pluripotent and can theoretically differentiate into all the tissues of the human body via the three primordial germ layers and the male and female germ lines. Currently, hESCs have been successfully converted in vitro into functional insulin secreting islets, cardiomyocytes, and neuronal cells and transfer of such cells into diabetic, ischaemic, and parkinsonian animal models respectively have shown successful engraftment. However, hESC-derived tissue application in the human is fraught with the problems of ethics, immunorejection, tumorigenesis from rogue undifferentiated hESCs, and inadequate cell numbers because of long population doubling times in hESCs. Human mesenchymal stem cells (hMSC) though not tumorigenic, also have their limitations of multipotency, immunorejection, and are currently confined to autologous transplantation with the genuine benefits in allogeneic settings not conclusively shown in large controlled human trials. Human Wharton's jelly stem cells (WJSC) from the umbilical cord matrix which are of epiblast origin and containing both hESC and hMSC markers appear to be less troublesome in not being an ethically controversial source, widely multipotent, not tumorigenic, maintain ''stemness'' for several serial passages and because of short population doubling time can be scaled up in large numbers. This report describes in detail the hurdles all these stem cell types have to overcome before stem cell-based therapy becomes a genuine reality.

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Section: Immunorejectionmentioning

confidence: 99%

Taking stem cells to the clinic: Major challenges

Bongso

Fong

Gauthaman

2008

J of Cellular Biochemistry

167

111

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“…However, this source of cells is plagued with severe ethical issues. The other negative side of ES is that proliferation and differentiation are largely uncontrolled, leading to the formation of teratomas (Cao et al, 2000;Fujikawa et al, 2005;Erdo et al, 2003). While there is a significant effort to decipher and control the mechanisms governing the behavior and differentiation of ESC (Baharvand et al, 2007), the results are far from satisfactory, eliminating the possibility of prompt clinical applications of ESC.…”

Section: Why We Are Interested In Human Umbilical Cord Blood (Hucb) -mentioning

confidence: 99%

A novel, neural potential of non-hematopoietic human umbilical cord blood stem cells

Domanska-Janik¹,

Bużañska²,

Łukomska³

2008

Int. J. Dev. Biol.

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From the time of discovery that among the cord blood mononuclear cell population there are cells capable of changing their fate towards the neural lineage and producing functional neurons and macroglial cells, our attempts have been focused on the understanding of the underlying mechanism of this transition. We have deciphered the first steps of neural stem/ progenitor gene induction in aggregating culture of cord blood mononuclear cells, their rapid phenotypic conversion under the influence of neuromorphogenic signals due to mitogen activation and their ability to expand and develop a prototypic, long-living line with neural stem cell properties. Evidence has accumulated that human umbilical cord-derived and neurally committed cells, due to their capacity for self-renewal, multilineage differentiation, plasticity and ability for long-lasting growth in vitro, provide unique material for the cell therapy of a wide spectrum of neurological diseases. The putative regenerating potential of these cord blood-derived neural stem/progenitor cells was evaluated after transplantation in experimental models of brain injury. In spite of initial promising data, the results indicate an urgent need to improve available animal model protocols in order to increase immuno-tolerance toward transplanted human cells.

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“…In experiments in which NOD mice were used as a model for type 1 diabetes, transplantation of wild-type bone marrow lowered blood sugar if the transplant was performed before, but not after, the onset of hyperglycemia (12). Also, murine embryonic stem cells differentiated to synthesize insulin and lowered blood sugar in STZ-induced diabetic mice, but the cells produced tumors (13).…”

mentioning

confidence: 99%

Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/ scid mice

Lee

Seo

Reger

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

670

556

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We tested the hypothesis that multipotent stromal cells from human bone marrow (hMSCs) can provide a potential therapy for human diabetes mellitus. Severe but nonlethal hyperglycemia was produced in NOD͞scid mice with daily low doses of streptozotocin on days 1-4, and hMSCs were delivered via intracardiac infusion on days 10 and 17. The hMSCs lowered blood glucose levels in the diabetic mice on day 32 relative to untreated controls (18.34 mM ؎ 1.12 SE vs. 27.78 mM ؎ 2.45 SE, P ‫؍‬ 0.0019). ELISAs demonstrated that blood levels of mouse insulin were higher in the hMSC-treated as compared with untreated diabetic mice, but human insulin was not detected. PCR assays detected human Alu sequences in DNA in pancreas and kidney on day 17 or 32 but not in other tissues, except heart, into which the cells were infused. In the hMSC-treated diabetic mice, there was an increase in pancreatic islets and ␤ cells producing mouse insulin. Rare islets contained human cells that colabeled for human insulin or PDX-1. Most of the ␤ cells in the islets were mouse cells that expressed mouse insulin. In kidneys of hMSC-treated diabetic mice, human cells were found in the glomeruli. There was a decrease in mesangial thickening and a decrease in macrophage infiltration. A few of the human cells appeared to differentiate into glomerular endothelial cells. Therefore, the results raised the possibility that hMSCs may be useful in enhancing insulin secretion and perhaps improving the renal lesions that develop in patients with diabetes mellitus.insulin ͉ pancreas ͉ streptozotocin ͉ transplantation P revious publications presented conflicting observations as to whether cells from bone marrow can provide a potential therapy for diabetes mellitus. One strategy (1-4) was to differentiate plastic adherent marrow cells in culture into insulin-secreting cells. A second strategy was to transplant diabetic mice with genetically labeled marrow and to search for labeled insulinproducing cells in the recipient mice. One study using a CRELoxP-GFP system found that 1.7-3% of the cells in islets of the recipient mice were marrow-derived and that GFP-labeled donor cells isolated from the islets expressed insulin, glucose transporter 2, and transcription factors typically found in ␤ cells (5). Three subsequent reports in which mice were transplanted with GFPexpressing bone marrow did not find evidence of marrow cells becoming insulin-producing cells in the pancreas of recipient mice (6-8), but in the reports it was difficult to exclude the possibility that the GFP gene was inactivated or that GFP-labeled cells were destroyed as they engrafted into islets. A third strategy was to determine whether systemically administered marrow cells enhanced regeneration of pancreatic insulin-producing cells in diabetic models. Hess et al. (9) reported that in NOD͞scid mice in which diabetes was induced with streptozotocin (STZ), partial marrow ablation followed by transplantation of either GFP-labeled whole-marrow or GFP-labeled c-kit ϩ cells from murine marrowenhanced r...

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Teratoma Formation Leads to Failure of Treatment for Type I Diabetes Using Embryonic Stem Cell-Derived Insulin-Producing Cells

Cited by 292 publications

References 37 publications

Taking stem cells to the clinic: Major challenges

Taking stem cells to the clinic: Major challenges

A novel, neural potential of non-hematopoietic human umbilical cord blood stem cells

Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/ scid mice

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