Teratoma Risk Research Articles

A Scalable Approach to Prevent Teratoma Formation of Human Embryonic Stem Cells

As the renewable source of all cell types in the body, human embryonic stem cells (hESCs) hold great promise for human cell therapy. However, one major bottleneck that hinders the clinic application of hESCs is that hESCs remaining with their differentiated derivatives pose cancer risk by forming teratomas after transplantation. NANOG is a critical pluripotency factor specifically expressed in hESCs but rarely in their differentiated derivatives. By introducing a hyperactive variant of herpes simplex virus thymidine kinase gene into the 3'-untranslated region of the endogenous NANOG gene of hESCs through homologous recombination, we developed a safe and highly scalable approach to efficiently eliminate the teratoma risk associated with hESCs without apparent negative impact on their differentiated cell types. As thymidine kinase is widely used in human gene therapy trials and is the therapeutic target of U. S. Food and Drug Administration-approved drugs, our strategy could be effectively applied to the clinic development of hESC-based human cell therapy.

Avances en uro-oncología «Oncoforum»: lo mejor de 2011

ObjectiveTo put forth new findings in urologic oncology with impact in the clinical practice, presented in the principal annual meetings (EAU, ESTRO, AUA, ASCO and ASTRO). MethodsThe reporters of the OncoUrology Forum select and classify the summaries on genitourinary cancer based on the impact on present or future practice. This document includes the summaries having the highest scores. ResultsThe OncoUrology Forum committee considered the following messages important. The PIVOT study shows that radical prostatectomy reduces the specific mortality of prostate cancer (PCa) compared to follow-up in observation, in localized high risk PCa or PSA >10ng/mL. Dissection of the pelvic lymph nodes should be done in all the patients with bladder cancer treated by radical cystectomy, regardless of the tumor stage, in accordance with baseline analysis of the Surveillance, Epidemiology and End Results (SEER) data. An analysis of the SEER of patients with renal cancer concluded that the radical nephrectomy is associated to worse cardiovascular and overall survival compared to those treated with partial nephrectomy in localized renal cell carcinoma of ≤2cm. In patients with nonseminomatous germ cells cancer, retroperitoneal lymph node dissection should not be omitted when the residual tumor size is ≤1cm because of the considerably high risk of teratoma and viable cancer. ConclusionsAlthough these studies do not offer a final response for all the oncourological subjects, these results will have an impact on the daily clinical practice.

Challenges to the clinical application of pluripotent stem cells: towards genomic and functional stability

Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and are pluripotent, retaining the ability to differentiate into all cell types in the body. As a renewable source of various types of human cells, hESCs hold great therapeutic potential. Although significant advances have been achieved in defining the conditions needed to differentiate hESCs into various types of biologically active cells, many challenges remain in the clinical development of hESC-based cell therapy, such as the immune rejection of allogeneic hESC-derived cells by recipients. Breakthroughs in the generation of induced pluripotent stem cells (iPSCs), which are reprogrammed from somatic cells with defined factors, raise the hope that autologous cells derived from patient-specific iPSCs can be transplanted without immune rejection. However, recent genomic studies have revealed epigenetic and genetic abnormalities associated with induced pluripotency, a risk of teratomas, and immunogenicity of some iPSC derivatives. These findings have raised safety concerns for iPSC-based therapy. Here, we review recent advances in understanding the genomic and functional stability of human pluripotent stem cells, current challenges to their clinical application and the progress that has been made to overcome these challenges.

Composite Cell Sheets

The safety and efficacy of myocardial regeneration using embryonic stem cells are limited by the risk of teratoma and the high rate of cell death. To address these issues, we developed a composite construct made of a sheet of adipose tissue-derived stroma cells and embryonic stem cell-derived cardiac progenitors. Ten Rhesus monkeys underwent a transient coronary artery occlusion followed, 2 weeks later, by the open-chest delivery of the composite cell sheet over the infarcted area or a sham operation. The sheet was made of adipose tissue-derived stroma cells grown from a biopsy of autologous adipose tissue and cultured onto temperature-responsive dishes. Allogeneic Rhesus embryonic stem cells were committed to a cardiac lineage and immunomagnetically sorted to yield SSEA-1(+) cardiac progenitors, which were then deposited onto the cell sheet. Cyclosporine was given for 2 months until the animals were euthanized. Preimplantation studies showed that the SSEA-1(+) progenitors expressed cardiac markers and had lost pluripotency. After 2 months, there was no teratoma in any of the 5 cell-treated monkeys. Analysis of >1500 histological sections showed that the SSEA-1(+) cardiac progenitors had differentiated into cardiomyocytes, as evidenced by immunofluorescence and real-time polymerase chain reaction. There were also a robust engraftment of autologous adipose tissue-derived stroma cells and increased angiogenesis compared with the sham animals. These data collected in a clinically relevant nonhuman primate model show that developmentally restricted SSEA-1(+) cardiac progenitors appear to be safe and highlight the benefit of the epicardial delivery of a construct harboring cells with a cardiomyogenic differentiation potential and cells providing them the necessary trophic support.

Embryonic Porcine Skin Precursors Can Successfully Develop into Integrated Skin without Teratoma Formation Posttransplantation in Nude Mouse Model

How to improve the wound healing quality of severe burn patients is still a challenge due to lack of skin appendages and rete ridges, no matter how much progress has been made in the fields of either stem cell or tissue engineering. We thus systematically studied the growth potential and differentiation capacity of porcine embryonic skin precursors. Implantation of embryonic skin precursors (PESPs) of different gestational ages in nude mice can generate the integrity skin, including epidermis, dermis and skin appendages, such as sweat gland, hair follicle, sebaceous gland, etc.. PESPs of embryonic day 42 possess the maximal growth potential, while, the safe window time of PESPs transplantation for prevention of teratoma risk is E56 or later. In conclusion, PESPs can form the 3 dimensional structures of skin with all necessary skin appendages. Our data strongly indicate that porcine embryonic skin precursors harvested from E56 of minipig may provide new hope for high-quality healing of extensive burns and traumas.

Management of good-risk metastatic nonseminomatous germ cell tumors of the testis: current concepts and controversies.

Introduction/Methods:Approximately 30% of nonseminomatous germ-cell tumors (NSGCT) of the testis present with metastatic disease. In 1997, the International Germ Cell Cancer Collaborative Group (IGCCCG) stratified all patients with metastatic NSGCT into various risk groups based on serum tumor markers and presence of visceral disease. We review the literature and present optimal stage-dependent management strategies in patients with favorable-risk metastatic NSGCT.Results:Primary chemotherapy (3 cycles BEP or 4 cycles EP) has been shown to be the preferred modality in patients with Clinical Stage IS (cIS) and in patients with bulky metastatic disease (≥CS IIb) due to their high risk of systemic disease and recurrence. Primary retroperitoneal lymph node dissection appears to be the most efficient primary therapy for retroperitoneal disease <2 cm (CS IIa), with adjuvant chemotherapy reserved for patients who are pathologically advanced (>5 nodes involved, single node > 2 cm) and for those who are non-compliant with surveillance regimens. Following primary chemotherapy, STM and radiographic evaluation are used to assess treatment response. For patients with normalization of STM and retroperitoneal masses < 1 cm, retroperitoneal lymph node dissection or observation with treatment at disease progression are considered options. Due to risk of teratoma or chemoresistant GCT, masses >1 cm and extra-retroperitoneal masses should be treated with surgical resection, which should be performed with nerve-sparing, if possible.Conclusions:In patients with favorable disease based on IGCCCG criteria, clinical stage, STM, and radiographic evaluation are used to guide appropriate therapy to provide excellent long-term cure rates (>92%) in patients with metastatic NSGCT.

Microvascular Tubes Derived from Embryonic Stem Cells Sustain Blood Flow

Since the introduction of somatic cell nuclear transfer (SCNT), therapeutic cloning has been brought closer to reality. Among the potential applications of therapeutic cloning is therapeutic angiogenesis. Although recent progress has been made with clinical therapeutic angiogenesis, it has met with limited success. One reason for this limitation has been the cell types used to generate the collateral vessels used for shunting around coronary blockages. Consequently, we developed a procedure using the embryonic stem (ES) cell model system to generate microvascular tubes similar to small vessels found in vivo. We then evaluated their ability to graft and sustain blood flow by transplanting them onto enhanced green fluorescent protein (eGFP)-expressing embryonic day-9 (E9) embryo hearts. Microvascular tubes generated from ES cells have not been thoroughly tested for their ability to graft and function within the heart, primarily because of issues including immune rejection of the foreign cells comprising collateral vessels and limited methodologies to prevent teratoma risk. However, because recent therapeutic cloning techniques have provided evidence of diminished risk of immune rejection, we improved the methodology for generating and isolating tubes from ES cells to evaluate their applicability for therapeutic angiogenesis. Here, we demonstrate that microvascular tubes generated from ES cells are capable of grafting onto E9-day embryo hearts and sustaining the flow of blood cells as verified by eGFP-expressing blood cells within non-eGFP ES cell-derived microvascular tubes.