Highly sensitive biosafety model for stem-cell-derived grafts

Taking stem cells to the clinic: Major challenges

“…The longer hESCs are differentiated in vitro, the risk of teratoma formation seems to be reduced. Other sensitive animal models for testing the proliferative potential of hESC grafts have also been suggested [Lawrenz et al, 2004]. These workers injected defined numbers of mESCs together with non-neoplastic MRC-5 cells into genetically bred nude mice.…”

“…As regards the sensitivity of the approach, it was shown that when a minimum of 2 million mESCs were injected into the left flank of nude mice, 60% of the mice developed teratomas [Lawrenz et al, 2004]. Thus, when setting up a sensitive teratoma assay, several important parameters need to be studied such as injection site, route of delivery, dosage, time range, and accurate recording of false positive and negative results with proper positive and negative controls.…”

Safety Assessment of Reprogrammed Cells Prior to Clinical Applications: Potential Approaches to Eliminate Teratoma Formation

“…Therefore, it will be essential to be able to monitor if any undifferentiated pluripotent cells remain after differentiation protocols, and if so, remove them without damaging the potentially therapeutic differentiated cells. Evidence supporting this statement is that it is known that the numbers of pluripotent cells injected experimentally have a directly proportional effect on how fast the teratomas develop and the size of the tumour [11][12][13]. It has also been reported that at doses of 1,000 pluripotent cells, teratomas developed with 40% efficiency but with 10,000 cells the efficiency increased to 100% [12].…”

“…It has also been reported that at doses of 1,000 pluripotent cells, teratomas developed with 40% efficiency but with 10,000 cells the efficiency increased to 100% [12]. However, as few as two pluripotent cells have been reported to induce teratoma formation in immuno-deficient mice, although with lower efficiency [11]. Taken together, this might mean that one remaining pluripotent stem cell in a patient bound cell preparation could lead to teratoma formation.…”

Self-Renewal, Pluripotency and Tumorigenesis in Pluripotent Stem Cells Revisited

“…However, this cellular ability is the major critical safety issue hampering the therapeutic application of human iPSCs (Yamanaka, 2009). According to Lawrenz et al (2004), two mouse ESCs were sufficient able to grow into a teratoma only when mixed with 2 x 10 6 non-tumorigenic fibroblasts (MRC-5) prior to transplantation into immunocompromised mice. To date, little is known about the tumorigenic property of PSCs, except that the oncogene Eras is responsible for the tumor-like growth of mouse ESCs .…”