Abstract
Human induced pluripotent stem cells (iPSCs) and derived progeny provide invaluable regenerative platforms, yet their clinical translation has been compromised by their biosafety concern. Here, we assessed the safety of transplanting patient-derived iPSC-generated pancreatic endoderm/ progenitor cells. Transplantation of progenitors from iPSCs reprogrammed by lentiviral vectors (LV-iPSCs) led to the formation of invasive teratocarcinoma-like tumors in more than 90% of immunodeficient mice. Moreover, removal of primary tumors from LV-iPSC progeny-transplanted hosts generated secondary and metastatic tumors. Combined transgene-free (TGF) reprogramming and elimination of residual pluripotent cells by enzymatic dissociation ensured tumor-free transplantation, ultimately enabling regeneration of type 1 diabetes-specific human islet structures in vivo. The incidence of tumor formation in TGF-iPSCs was titratable, depending on the oncogenic load, with reintegration of the cMYC expressing vector abolishing tumor-free transplantation. Thus, transgenefree cMYC-independent reprogramming and elimination of residual pluripotent cells are mandatory steps in achieving transplantation of iPSC progeny for customized and safe islet regeneration in vivo.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 694-702 |
| Number of pages | 9 |
| Journal | Stem cells translational medicine |
| Volume | 5 |
| Issue number | 5 |
| DOIs | |
| State | Published - 2016 |
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Keywords
- Insertional mutagenesis
- Integration
- iPS cells
- Teratoma
- Type 1 diabetes
ASJC Scopus subject areas
- Cell Biology
- Developmental Biology
Cite this
Tumor-free transplantation of Patient-Derived induced pluripotent stem cell progeny for customized islet regeneration. / El Khatib, Moustafa M.; Ohmine, Seiga; Jacobus, Egon J.; Tonne, Jason M.; Morsy, Salma G.; Holditch, Sara J.; Schreiber, Claire A.; Uetsuka, Koji; Fusaki, Noemi; Wigle, Dennis A; Terzic, Andre; Kudva, Yogish C; Ikeda, Yasuhiro H.
In: Stem cells translational medicine, Vol. 5, No. 5, 2016, p. 694-702.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tumor-free transplantation of Patient-Derived induced pluripotent stem cell progeny for customized islet regeneration
AU - El Khatib, Moustafa M.
AU - Ohmine, Seiga
AU - Jacobus, Egon J.
AU - Tonne, Jason M.
AU - Morsy, Salma G.
AU - Holditch, Sara J.
AU - Schreiber, Claire A.
AU - Uetsuka, Koji
AU - Fusaki, Noemi
AU - Wigle, Dennis A
AU - Terzic, Andre
AU - Kudva, Yogish C
AU - Ikeda, Yasuhiro H
PY - 2016
Y1 - 2016
N2 - Human induced pluripotent stem cells (iPSCs) and derived progeny provide invaluable regenerative platforms, yet their clinical translation has been compromised by their biosafety concern. Here, we assessed the safety of transplanting patient-derived iPSC-generated pancreatic endoderm/ progenitor cells. Transplantation of progenitors from iPSCs reprogrammed by lentiviral vectors (LV-iPSCs) led to the formation of invasive teratocarcinoma-like tumors in more than 90% of immunodeficient mice. Moreover, removal of primary tumors from LV-iPSC progeny-transplanted hosts generated secondary and metastatic tumors. Combined transgene-free (TGF) reprogramming and elimination of residual pluripotent cells by enzymatic dissociation ensured tumor-free transplantation, ultimately enabling regeneration of type 1 diabetes-specific human islet structures in vivo. The incidence of tumor formation in TGF-iPSCs was titratable, depending on the oncogenic load, with reintegration of the cMYC expressing vector abolishing tumor-free transplantation. Thus, transgenefree cMYC-independent reprogramming and elimination of residual pluripotent cells are mandatory steps in achieving transplantation of iPSC progeny for customized and safe islet regeneration in vivo.
AB - Human induced pluripotent stem cells (iPSCs) and derived progeny provide invaluable regenerative platforms, yet their clinical translation has been compromised by their biosafety concern. Here, we assessed the safety of transplanting patient-derived iPSC-generated pancreatic endoderm/ progenitor cells. Transplantation of progenitors from iPSCs reprogrammed by lentiviral vectors (LV-iPSCs) led to the formation of invasive teratocarcinoma-like tumors in more than 90% of immunodeficient mice. Moreover, removal of primary tumors from LV-iPSC progeny-transplanted hosts generated secondary and metastatic tumors. Combined transgene-free (TGF) reprogramming and elimination of residual pluripotent cells by enzymatic dissociation ensured tumor-free transplantation, ultimately enabling regeneration of type 1 diabetes-specific human islet structures in vivo. The incidence of tumor formation in TGF-iPSCs was titratable, depending on the oncogenic load, with reintegration of the cMYC expressing vector abolishing tumor-free transplantation. Thus, transgenefree cMYC-independent reprogramming and elimination of residual pluripotent cells are mandatory steps in achieving transplantation of iPSC progeny for customized and safe islet regeneration in vivo.
KW - Insertional mutagenesis
KW - Integration
KW - iPS cells
KW - Teratoma
KW - Type 1 diabetes
UR - http://www.scopus.com/inward/record.url?scp=84964277366&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964277366&partnerID=8YFLogxK
U2 - 10.5966/sctm.2015-0017
DO - 10.5966/sctm.2015-0017
M3 - Article
C2 - 26987352
AN - SCOPUS:84964277366
VL - 5
SP - 694
EP - 702
JO - Stem cells translational medicine
JF - Stem cells translational medicine
SN - 2157-6564
IS - 5
ER -