Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition

doi:10.1016/j.stemcr.2015.01.006

. 2015 Mar 10;4(3):360-73.

doi: 10.1016/j.stemcr.2015.01.006. Epub 2015 Feb 13.

Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition

Satoshi Nori¹, Yohei Okada², Soraya Nishimura¹, Takashi Sasaki³, Go Itakura¹, Yoshiomi Kobayashi¹, Francois Renault-Mihara¹, Atsushi Shimizu⁴, Ikuko Koya⁵, Rei Yoshida⁶, Jun Kudoh⁷, Masato Koike⁸, Yasuo Uchiyama⁸, Eiji Ikeda⁹, Yoshiaki Toyama⁶, Masaya Nakamura¹⁰, Hideyuki Okano¹¹

Affiliations

¹ Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
² Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Kanrinmaru Project, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
³ Center for Integrated Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
⁴ Department of Molecular Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
⁵ Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
⁶ Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
⁷ Laboratory of Gene Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
⁸ Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyoku, Tokyo 113-8421, Japan.
⁹ Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Pathology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
¹⁰ Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. Electronic address: masa@a8.keio.jp.
¹¹ Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. Electronic address: hidokano@a2.keio.jp.

PMID: 25684226
PMCID: PMC4375796
DOI: 10.1016/j.stemcr.2015.01.006

Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition

Satoshi Nori et al. Stem Cell Reports. 2015.

. 2015 Mar 10;4(3):360-73.

doi: 10.1016/j.stemcr.2015.01.006. Epub 2015 Feb 13.

Authors

Affiliations

¹ Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
² Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Kanrinmaru Project, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
³ Center for Integrated Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
⁴ Department of Molecular Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
⁵ Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
⁶ Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
⁷ Laboratory of Gene Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
⁸ Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyoku, Tokyo 113-8421, Japan.
⁹ Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Pathology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
¹⁰ Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. Electronic address: masa@a8.keio.jp.
¹¹ Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. Electronic address: hidokano@a2.keio.jp.

PMID: 25684226
PMCID: PMC4375796
DOI: 10.1016/j.stemcr.2015.01.006

Abstract

Previously, we described the safety and therapeutic potential of neurospheres (NSs) derived from a human induced pluripotent stem cell (iPSC) clone, 201B7, in a spinal cord injury (SCI) mouse model. However, several safety issues concerning iPSC-based cell therapy remain unresolved. Here, we investigated another iPSC clone, 253G1, that we established by transducing OCT4, SOX2, and KLF4 into adult human dermal fibroblasts collected from the same donor who provided the 201B7 clone. The grafted 253G1-NSs survived, differentiated into three neural lineages, and promoted functional recovery accompanied by stimulated synapse formation 47 days after transplantation. However, long-term observation (for up to 103 days) revealed deteriorated motor function accompanied by tumor formation. The tumors consisted of Nestin(+) undifferentiated neural cells and exhibited activation of the OCT4 transgene. Transcriptome analysis revealed that a heightened mesenchymal transition may have contributed to the progression of tumors derived from grafted cells.

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Figures

**Figure 1**
Grafted 253G1-NSs Mainly Differentiate into Neurons and Form Synapses with Host Spinal Cord Neurons (A and B) Venus⁺ 253G1-NSs integrated into the mouse spinal cord. Arrowheads indicate the lesion epicenter. (C–F) Representative images of Venus⁺ grafted cells immunostained for the markers NeuN (mature neurons) (C), βIII tubulin (all neurons) (D), GFAP (astrocytes) (E), and APC (oligodendrocytes) (F). (G) Percentages of cell-type-specific marker-positive cells among Venus⁺ grafted cells at 47 days post-transplantation. Values are expressed as the mean ± SEM (n = 4 mice). (H) Most 253G1-derived neurons differentiated into GAD67⁺ (GABAergic) neurons. (I and J) TH⁺/HNu⁺ neurons and ChAT⁺/HNu⁺ neurons were observed, but were rare. (K) Sections were triple stained for HNu (green), βIII tubulin (red), and the presynaptic marker Bassoon (Bsn, white). The Bsn antibody recognized the mouse, but not the human, protein. (L) Sections triple stained for HNu (green), βIII tubulin (red), and the human-specific presynaptic marker hSyn (white). βIII tubulin⁺/HNu⁻ neurons represented host mouse neurons. The hSyn antibody recognized the human, but not the mouse, protein. (M) Large numbers of somatic and dendritic terminals from graft-derived nerve cells were present on host ChAT⁺ motor neurons at the ventral horns. (N) Electron microscopy (EM) images show synapse formation between host mouse neurons and graft-derived Venus⁺ (black) human neurons. Pre- and post-synaptic structures indicate transmission from a graft-derived neuron to a host neuron, and from a host neuron to a graft-derived neuron. H, host neuron; G, graft-derived neuron; arrowheads, post-synaptic density. (O) Motor function in the hind limbs was assessed weekly using the BMS score until 47 days post-transplantation. Values are expressed as the mean ± SEM (n = 32 mice). (P) Rotarod test 47 days after transplantation. Graph shows total run time. Values are expressed as the means ± SEM (n = 10 mice). (Q) Treadmill gait analysis using the DigiGait system 47 days post-transplantation. Graph shows stride length. Values are expressed as the means ± SEM (n = 19 mice). Behavioral analyses were performed by two observers who were blinded to the treatment conditions. Scale bars, 1,000 μm in (A); 100 μm in (B); 50 μm in (J-1); 20 μm in (F-3), (F-4), (H-1), (J-2), (K-1), (L-1), and (M-1); 10 μm in (H-2), (J-3), (K-2), (L-2), and (M-2); 0.5 μm in (N). See also Figure S1.

**Figure 2**
Tumor Formation during Long-Term Observation after 253G1-NS Transplantation (A) Up to 103 days post-transplantation, motor function in the hind limbs was assessed weekly using the BMS score. Values are expressed as the means ± SEM (n = 32 mice up to 47 days post-transplantation; thereafter, n = 22 mice until 103 days post-transplantation). (B) Representative in vivo images of mice at 0, 14, 42, 70, and 103 days after 253G1-NS transplantation. (C) Quantitative analysis of photon counts derived from grafted cells. Values are expressed as the means ± SEM (n = 20 mice up to 42 days post-transplantation; thereafter, n = 14 mice until 103 days post-transplantation). (D) Representative hematoxylin and eosin (H&E) image of a large tumor (700 μm < ϕ). (E) Boxed area in (D). (E1–E3) Immunohistochemistry showing that most grafted cells in the microcystic area were Nestin⁺. (F) Representative H&E image of a medium tumor (200 < ϕ < 700 μm). (G) Boxed area in (F). Immunohistochemistry shows that some grafted cells exhibited normal neural differentiation. (H and I) Boxed area in (F). Some grafted cells formed microcystic masses that were positive for Nestin. (J) Percentages of cell-type-specific, marker-positive cells among HNu⁺ grafted cells at 103 days post-transplantation. Values represent the means ± SEM (n = 4 and 10 mice for 47 and 103 days post-transplantation, respectively). ^∗p < 0.05, ^∗∗p < 0.01. Scale bars, 500 μm in (D) and (F), 50 μm in (E) and (G–I). See also Figure S2.

**Figure 3**
Histological and Gene-Expression Analyses of Tumors (A) Schematic of histological analyses of tumors. (B) Correlation between tumor diameter and the proportion of grafted cells that were Nestin⁺ at 47 and 103 days post-transplantation (TP). (C) Correlation between tumor diameter and the proportion of grafted cells that were Ki-67⁺. (D) Correlation between tumor diameter and the proportion of grafted cells that were OCT4⁺. (E) Correlation between the tumor diameter and the proportion of grafted cells that were OCT4⁺/HNu⁺ at 103 days after TP. (F) Correlation between the number of days after TP (47 or 103 days after TP) and the proportion of grafted cells that were OCT4⁺. In (B)–(F), n indicates the number of mice. (G) Schematic of mRNA expression analyses of tumors. (H–M) The expression of human *OCT4*-Tg, *OCT4*-Endo, *SOX2*-Tg, *SOX2*-Endo, *KLF4*-Tg, *KLF4*-Endo, c-*MYC*-Tg, and *c-MYC*-Endo mRNA in 253G1 cells, 253G1-NSs, 103-day post-transplant 253G1-NSs (TP 103d), and adult human dermal fibroblasts (HDFs) was analyzed by RT-PCR. Data are presented as expression levels relative to the control (HDFs) 11 days after retroviral transduction of *OCT4*, *SOX2*, *KLF4*, and *c-MYC*. Values represent the means ± SEM (n = 3 independent experiments). The p values shown in (B)–(F) were calculated using Scheffe’s test, and p values to determine significance were calculated using the Kruskal-Wallis non-parametric test: (B) 5.00E-06, (C) 7.20E-06, (D) 0.01, and (F) 1.33E-04. ^∗p < 0.05, ^∗∗p < 0.01. ns, non-significant.

**Figure 4**
Global Human Gene-Expression Analysis (A) Hierarchical clustering analysis of mouse gene-expression data from spinal cord tissues of the PBS-5d and -103d, 253G1-NS/TP-5d and -103d, and 201B7-NS/TP-5d and -103d groups. (B) Hierarchical clustering analysis of human gene-expression data: 253G1-NSs and 201B7-NSs, as well as spinal cord tissues of the 253G1-NS/TP-5d and -103d, and 201B7-NS/TP-5d and -103d groups. In (A) and (B), the signal intensity of each gene is displayed as a heatmap colored according to the expression level. (C) Principal-component analysis (PCA) of human gene-expression data. x axis, component 1 (41.03%); y axis, component 2 (24.21%); z axis, component 3 (13.88%). (D) Two-dimensional PCA of human gene expression data. x axis, component 1 (41.03%); y axis, component 2 (24.21%). (E) Venn diagram of human genes whose expression increased in the 253G1-NS/TP-103d and 201B7-NS/TP-103d groups relative to 253G1-NSs and 201B7-NSs. Color key: red, 692 genes highly expressed in the 253G1-NS/TP-103d group; blue, 335 genes highly expressed in the 201B7-NS/TP-103d group; purple, 1,023 genes highly expressed in both the 253G1- and 201B7-NS/TP-103d groups. (F–L) EMT-related human gene expression in 253G1- and 201B7-NSs and the 253G1- and 201B7-NS/TP-103d groups. Values represent the means ± SEM (n = 1 each in the human iPSC-NS, n = 2 for 201B7-NS/TP-103d, and n = 3 for 253G1-NS/TP-103d; n indicates the number of independent experiments). (M–P) The expression of *SNAI1*, *SNAI2*, *TWIST1,* and *TWIST2* mRNA in 201B7-NSs and 253G1-NSs was analyzed by RT-PCR. Data are presented as expression levels relative to the control (the U87 human glioblastoma cell line). Values represent the means ± SEM (n = 3 independent experiments). (Q) Representative H&E image of the mid-sagittal section 103 days after transplantation. (R) p-STAT3-stained image of the adjacent section of (Q). Arrow, lesion epicenter; arrowhead, distribution of grafted 253G1-NSs. (S) Boxed area in (R). Scale bar, 1,000 μm in (Q) and (R), 100 μm in (S). ^∗p < 0.05, ^∗∗p < 0.01. See also the mRNA-seq read distribution in Table S1.

**Figure 5**
The Most Significantly Altered Common Pathways after Transplantation of 253G1- and 201B7-NSs, as Revealed by Ingenuity Pathway Analysis Canonical pathway analysis identified the pathways from the Ingenuity Pathway Analysis library that were significantly enriched in the data set. Only genes that showed a fold change ≥ 3.0 were considered in this analysis. The black bars show the human gene set in the 253G1-NS/TP-103d group versus the 201B7-NS/TP-103d group. The white bars show the comparison of the human gene set in 253G1-NSs versus 201B7-NSs in the same pathway. Bars represent the logarithmic values (log₁₀) of the significance level (p); the solid line corresponds to the threshold of p = 0.05.

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References

1. Abou-Ghazal M., Yang D.S., Qiao W., Reina-Ortiz C., Wei J., Kong L.Y., Fuller G.N., Hiraoka N., Priebe W., Sawaya R., Heimberger A.B. The incidence, correlation with tumor-infiltrating inflammation, and prognosis of phosphorylated STAT3 expression in human gliomas. Clin. Cancer Res. 2008;14:8228–8235. - PMC - PubMed
1. Bowman T., Broome M.A., Sinibaldi D., Wharton W., Pledger W.J., Sedivy J.M., Irby R., Yeatman T., Courtneidge S.A., Jove R. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc. Natl. Acad. Sci. USA. 2001;98:7319–7324. - PMC - PubMed
1. Bradford J.R., Farren M., Powell S.J., Runswick S., Weston S.L., Brown H., Delpuech O., Wappett M., Smith N.R., Carr T.H. RNA-seq differentiates tumour and host mRNA expression changes induced by treatment of human tumour xenografts with the VEGFR tyrosine kinase inhibitor Cediranib. PLoS ONE. 2013;8:e66003. - PMC - PubMed
1. Cheng G.Z., Zhang W.Z., Sun M., Wang Q., Coppola D., Mansour M., Xu L.M., Costanzo C., Cheng J.Q., Wang L.H. Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J. Biol. Chem. 2008;283:14665–14673. - PMC - PubMed
1. Conway T., Wazny J., Bromage A., Tymms M., Sooraj D., Williams E.D., Beresford-Smith B. Xenome—a tool for classifying reads from xenograft samples. Bioinformatics. 2012;28:i172–i178. - PMC - PubMed

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[1] Abou-Ghazal M., Yang D.S., Qiao W., Reina-Ortiz C., Wei J., Kong L.Y., Fuller G.N., Hiraoka N., Priebe W., Sawaya R., Heimberger A.B. The incidence, correlation with tumor-infiltrating inflammation, and prognosis of phosphorylated STAT3 expression in human gliomas. Clin. Cancer Res. 2008;14:8228–8235. - PMC - PubMed

[2] Abou-Ghazal M., Yang D.S., Qiao W., Reina-Ortiz C., Wei J., Kong L.Y., Fuller G.N., Hiraoka N., Priebe W., Sawaya R., Heimberger A.B. The incidence, correlation with tumor-infiltrating inflammation, and prognosis of phosphorylated STAT3 expression in human gliomas. Clin. Cancer Res. 2008;14:8228–8235. - PMC - PubMed

[3] Bowman T., Broome M.A., Sinibaldi D., Wharton W., Pledger W.J., Sedivy J.M., Irby R., Yeatman T., Courtneidge S.A., Jove R. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc. Natl. Acad. Sci. USA. 2001;98:7319–7324. - PMC - PubMed

[4] Bowman T., Broome M.A., Sinibaldi D., Wharton W., Pledger W.J., Sedivy J.M., Irby R., Yeatman T., Courtneidge S.A., Jove R. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc. Natl. Acad. Sci. USA. 2001;98:7319–7324. - PMC - PubMed

[5] Bradford J.R., Farren M., Powell S.J., Runswick S., Weston S.L., Brown H., Delpuech O., Wappett M., Smith N.R., Carr T.H. RNA-seq differentiates tumour and host mRNA expression changes induced by treatment of human tumour xenografts with the VEGFR tyrosine kinase inhibitor Cediranib. PLoS ONE. 2013;8:e66003. - PMC - PubMed

[6] Bradford J.R., Farren M., Powell S.J., Runswick S., Weston S.L., Brown H., Delpuech O., Wappett M., Smith N.R., Carr T.H. RNA-seq differentiates tumour and host mRNA expression changes induced by treatment of human tumour xenografts with the VEGFR tyrosine kinase inhibitor Cediranib. PLoS ONE. 2013;8:e66003. - PMC - PubMed

[7] Cheng G.Z., Zhang W.Z., Sun M., Wang Q., Coppola D., Mansour M., Xu L.M., Costanzo C., Cheng J.Q., Wang L.H. Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J. Biol. Chem. 2008;283:14665–14673. - PMC - PubMed

[8] Cheng G.Z., Zhang W.Z., Sun M., Wang Q., Coppola D., Mansour M., Xu L.M., Costanzo C., Cheng J.Q., Wang L.H. Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J. Biol. Chem. 2008;283:14665–14673. - PMC - PubMed

[9] Conway T., Wazny J., Bromage A., Tymms M., Sooraj D., Williams E.D., Beresford-Smith B. Xenome—a tool for classifying reads from xenograft samples. Bioinformatics. 2012;28:i172–i178. - PMC - PubMed

[10] Conway T., Wazny J., Bromage A., Tymms M., Sooraj D., Williams E.D., Beresford-Smith B. Xenome—a tool for classifying reads from xenograft samples. Bioinformatics. 2012;28:i172–i178. - PMC - PubMed

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Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition

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Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition

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