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Tumorigenicity studies of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration.
PLoS One. 2014; 9(1):e85336.Plos

Abstract

Basic studies of human pluripotential stem cells have advanced rapidly and stem cell products are now seeing therapeutic applications. However, questions remain regarding the tumorigenic potential of such cells. Here, we report the tumorigenic potential of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of wet-type, age-related macular degeneration (AMD). First, immunodeficient mouse strains (nude, SCID, NOD-SCID and NOG) were tested for HeLa cells' tumor-forming capacity by transplanting various cell doses subcutaneously with or without Matrigel. The 50% Tumor Producing Dose (TPD50 value) is the minimal dose of transplanted cells that generated tumors in 50% of animals. For HeLa cells, the TPD50 was the lowest when cells were embedded in Matrigel and transplanted into NOG mice (TPD50 = 10(1.1), n = 75). The TPD50 for undifferentiated iPSCs transplanted subcutaneously to NOG mice in Matrigel was 10(2.12); (n = 30). Based on these experiments, 1×10(6) iPSC-derived RPE were transplanted subcutaneously with Matrigel, and no tumor was found during 15 months of monitoring (n = 65). Next, to model clinical application, we assessed the tumor-forming potential of HeLa cells and iPSC 201B7 cells following subretinal transplantation of nude rats. The TPD50 for iPSCs was 10(4.73) (n = 20) and for HeLa cells 10(1.32) (n = 37) respectively. Next, the tumorigenicity of iPSC-derived RPE was tested in the subretinal space of nude rats by transplanting 0.8-1.5×10(4) iPSC-derived RPE in a collagen-lined (1 mm×1 mm) sheet. No tumor was found with iPSC-derived RPE sheets during 6-12 months of monitoring (n = 26). Considering the number of rodents used, the monitoring period, the sensitivity of detecting tumors via subcutaneous and subretinal administration routes and the incidence of tumor formation from the iPSC-derived RPE, we conclude that the tumorigenic potential of the iPSC-derived RPE was negligible.

Authors+Show Affiliations

Division of Cell Therapy, Foundation for Biomedical Research and Innovation, Kobe, Japan ; Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan.Division of Cell Therapy, Foundation for Biomedical Research and Innovation, Kobe, Japan.Division of Cell Therapy, Foundation for Biomedical Research and Innovation, Kobe, Japan.Division of Cell Therapy, Foundation for Biomedical Research and Innovation, Kobe, Japan.Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan.Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan ; Department of Ophthalmology, Kawasaki Medical School, Kurashiki, Okayama, Japan.Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan.Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan.Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan.Division of Cell Therapy, Foundation for Biomedical Research and Innovation, Kobe, Japan ; Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24454843

Citation

Kanemura, Hoshimi, et al. "Tumorigenicity Studies of Induced Pluripotent Stem Cell (iPSC)-derived Retinal Pigment Epithelium (RPE) for the Treatment of Age-related Macular Degeneration." PloS One, vol. 9, no. 1, 2014, pp. e85336.
Kanemura H, Go MJ, Shikamura M, et al. Tumorigenicity studies of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration. PLoS One. 2014;9(1):e85336.
Kanemura, H., Go, M. J., Shikamura, M., Nishishita, N., Sakai, N., Kamao, H., Mandai, M., Morinaga, C., Takahashi, M., & Kawamata, S. (2014). Tumorigenicity studies of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration. PloS One, 9(1), e85336. https://doi.org/10.1371/journal.pone.0085336
Kanemura H, et al. Tumorigenicity Studies of Induced Pluripotent Stem Cell (iPSC)-derived Retinal Pigment Epithelium (RPE) for the Treatment of Age-related Macular Degeneration. PLoS One. 2014;9(1):e85336. PubMed PMID: 24454843.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumorigenicity studies of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration. AU - Kanemura,Hoshimi, AU - Go,Masahiro J, AU - Shikamura,Masayuki, AU - Nishishita,Naoki, AU - Sakai,Noriko, AU - Kamao,Hiroyuki, AU - Mandai,Michiko, AU - Morinaga,Chikako, AU - Takahashi,Masayo, AU - Kawamata,Shin, Y1 - 2014/01/14/ PY - 2013/08/13/received PY - 2013/12/04/accepted PY - 2014/1/24/entrez PY - 2014/1/24/pubmed PY - 2014/9/18/medline SP - e85336 EP - e85336 JF - PloS one JO - PLoS One VL - 9 IS - 1 N2 - Basic studies of human pluripotential stem cells have advanced rapidly and stem cell products are now seeing therapeutic applications. However, questions remain regarding the tumorigenic potential of such cells. Here, we report the tumorigenic potential of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of wet-type, age-related macular degeneration (AMD). First, immunodeficient mouse strains (nude, SCID, NOD-SCID and NOG) were tested for HeLa cells' tumor-forming capacity by transplanting various cell doses subcutaneously with or without Matrigel. The 50% Tumor Producing Dose (TPD50 value) is the minimal dose of transplanted cells that generated tumors in 50% of animals. For HeLa cells, the TPD50 was the lowest when cells were embedded in Matrigel and transplanted into NOG mice (TPD50 = 10(1.1), n = 75). The TPD50 for undifferentiated iPSCs transplanted subcutaneously to NOG mice in Matrigel was 10(2.12); (n = 30). Based on these experiments, 1×10(6) iPSC-derived RPE were transplanted subcutaneously with Matrigel, and no tumor was found during 15 months of monitoring (n = 65). Next, to model clinical application, we assessed the tumor-forming potential of HeLa cells and iPSC 201B7 cells following subretinal transplantation of nude rats. The TPD50 for iPSCs was 10(4.73) (n = 20) and for HeLa cells 10(1.32) (n = 37) respectively. Next, the tumorigenicity of iPSC-derived RPE was tested in the subretinal space of nude rats by transplanting 0.8-1.5×10(4) iPSC-derived RPE in a collagen-lined (1 mm×1 mm) sheet. No tumor was found with iPSC-derived RPE sheets during 6-12 months of monitoring (n = 26). Considering the number of rodents used, the monitoring period, the sensitivity of detecting tumors via subcutaneous and subretinal administration routes and the incidence of tumor formation from the iPSC-derived RPE, we conclude that the tumorigenic potential of the iPSC-derived RPE was negligible. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24454843/Tumorigenicity_studies_of_induced_pluripotent_stem_cell__iPSC__derived_retinal_pigment_epithelium__RPE__for_the_treatment_of_age_related_macular_degeneration_ L2 - https://dx.plos.org/10.1371/journal.pone.0085336 DB - PRIME DP - Unbound Medicine ER -