In vivo maturation of human embryonic stem cell-derived teratoma over time

Akutsu, Hidenori; Nasu, Michiyo; Morinaga, Soichiro; Motoyama, Teiichi; Homma, Natsumi Y.; Machida, Masakazu; Yamazaki-Inoue, Mayu; Okamura, Koji; Nakabayashi, Kazuhiko; Takada, Shuji; Nakamura, Naoko; Kanzaki, Seiichi; Hata, Kenichiro; Umezawa, Akihiro

doi:10.1016/j.reth.2016.06.003

Cited by 19 publications

(13 citation statements)

References 22 publications

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“…Interestingly, Akutsu et al . reported that teratomas derived from hESCs histologically matured in vivo over time [ 27 ]. Therefore, the formation of immature teratomas in vivo is regarded as a quality attribute of hPSCs, and immaturity of teratomas largely depends on the duration of hPSC transplantation.…”

Section: Discussionmentioning

confidence: 99%

Tumorigenicity-associated characteristics of human iPS cell lines

et al. 2018

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Human induced pluripotent stem cells (hiPSCs) represent promising raw materials of human cell-based therapeutic products (hCTPs). As undifferentiated hiPSCs exhibit intrinsic tumorigenicity properties that enable them to form teratomas, hCTPs containing residual undifferentiated hiPSCs may cause tumor formation following transplantation. We first established quantitative and sensitive tumorigenicity testing of hiPSCs dissociated into single cells using NOD/Shi-scid IL2Rγnull (NOG) mice by inhibiting apoptosis of hiPSCs with a Rho kinase inhibitor. To examine different features in tumorigenicity of various hiPSCs, 10 commonly available hiPSC lines were subjected to in vivo tumorigenicity testing. Transplanted hiPSC lines showed remarkable variation in tumor incidence, formation latency, and volumes. Most of the tumors formed were classified as immature teratomas. However, no signs of malignancies, such as carcinoma and sarcoma, were recognized in the tumors. Characteristics associated tumorigenicity of hiPSCs were investigated with microarray analysis, karyotype analysis, and whole exome sequencing. Gene expression profiling and pathway analysis supported different features of hiPSC lines in tumorigenicity. hiPSC lines showed chromosomal abnormalities in some lines and 61–77 variants of cancer-related genes carrying effective nonsynonymous mutations, which were confirmed in the COSMIC databases. In this study, the chromosomal abnormalities and cancer-related gene mutations observed in hiPSC lines did not lead to the malignancy of tumors derived from hiPSCs. Our results suggest that the potential tumorigenicity risk of hCTPs containing residual undifferentiated hiPSCs is dependent on not only amounts of undifferentiated hiPSCs but also features of the cell lines used as raw materials, a finding that should be considered from the perspective of quality of hCTPs used.

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Section: Discussionmentioning

confidence: 99%

Tumorigenicity-associated characteristics of human iPS cell lines

et al. 2018

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“…For comparison, we used iPSCs of healthy and diseased donors. iPSCs such as PAE-iPSCs, UtE-iPSCs, AM-iPSCs, and 201B7 have been generated from placental, endometrial, amniotic, and fibroblastic cells [8,9,[31][32][33][34].…”

Section: Teratoma Formationmentioning

confidence: 99%

Gorlin syndrome-induced pluripotent stem cells form medulloblastoma with loss of heterozygosity in PTCH1

Ikemoto

Miyashita

Nasu

et al. 2020

Aging

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Gorlin syndrome is a rare autosomal dominant hereditary disease with a high incidence of tumors such as basal cell carcinoma and medulloblastoma. Disease-specific induced pluripotent stem cells (iPSCs) and an animal model have been used to analyze disease pathogenesis. In this study, we generated iPSCs derived from fibroblasts of four patients with Gorlin syndrome (Gln-iPSCs) with heterozygous mutations of the PTCH1 gene. Gln-iPSCs from the four patients developed into medulloblastoma, a manifestation of Gorlin syndrome, in 100% (four out of four), of teratomas after implantation into immunodeficient mice, but none (0/584) of the other iPSC-teratomas did so. One of the medulloblastomas showed loss of heterozygosity in the PTCH1 gene while the benign teratoma, i.e. the non-medulloblastoma portion, did not, indicating a close clinical correlation between tumorigenesis in Gorlin syndrome patients and Gln-iPSCs.

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“…SEES" ESCs were routinely cultured onto a feeder layer of freshly plated gamma-irradiated mouse embryonic fibroblasts (MEFs), isolated from ICR embryos at 12.5 gestations and passages 2 times before irradiation (30 Gy), in the ESC culture media [15,16]. The ESC media…”

Section: Culture Of Escs Ipscs and Hepatocytesmentioning

confidence: 99%

“…In this study, we propagated hepatocytes or hepatocyte-like cells derived from human PSC, i.e. ESCs and iPSCs, and enriched zone I hepatocytes with ammonia [15,16]. Ammonia-selected cells proliferated in vitro at least up to 30 population doublings for more than 190 days.…”

Section: Introductionmentioning

confidence: 99%

Ammonia-based enrichment and long-term propagation of zone I hepatocyte-like cells

Tsuneishi

Saku

Miyata

et al. 2020

Preprint

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Zone I and zone III hepatocytes metabolize ammonia through urea cycle and drug by cytochrome P450, respectively. Ammonia has a cytotoxic effect, and can therefore be used as a selection agent for enrichment of hepatocytes. Besides, isolated hepatocytes from livers can be propagated ex vivo under appropriate condition. However, it has not been investigated so far whether ammonia-treated hepatocyte-like cells are able to proliferate in vitro. In this study, we employed the ammonia selection strategy to purify hepatocyte-like cells that were differentiated from human pluripotent stem cells (PSCs) that are embryonic stem cells (ESCs) and induced pluripotent stem cells. Hepatocyte-like cells after exposure to ammonia highly expressed the CPS1 gene that metabolizes ammonia to carbamoyl phosphate. The resistance to cytotoxicity or cell death by ammonia is probably attributed to the metabolic activity of ammonia in the cells. In addition to the ammonia metabolism-related genes, ammonia-selected PSC-derived hepatocytes increased expression of the CYP3A4 gene, one of the cytochrome P450 genes, that is mainly expressed in zone III hepatocytes. Ammonia-selected hepatocyte-like cells derived from both ESCs and iPSCs can be propagated in vitro up to 30 population doublings for more than 190 days without affecting expression of the liver-associated genes, implying that the ammoniaselected cells have immortality or equivalent life span on the appropriate feeder cells like ESCs and iPSCs. The long-term cultivation of ammonia-selected hepatocyte-like cells resulted in the increased expression of hepatocyte-associated genes such as the CPS1 and CYP3A4 genes. The ammonia selection method to enrich a hepatocyte population was also applicable to immortalized cells from the liver. Ammonia treatment in combination with in vitro propagation will be used to obtain large amounts of hepatocytes or hepatocyte-like cells for pharmacology, toxicology and regenerative medicine.

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In vivo maturation of human embryonic stem cell-derived teratoma over time

Cited by 19 publications

References 22 publications

Tumorigenicity-associated characteristics of human iPS cell lines

Tumorigenicity-associated characteristics of human iPS cell lines

Gorlin syndrome-induced pluripotent stem cells form medulloblastoma with loss of heterozygosity in PTCH1

Ammonia-based enrichment and long-term propagation of zone I hepatocyte-like cells

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