Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells
Ex vivo gene therapy (GT) is a promising treatment for inherited genetic diseases. An ideal transduction protocol should determine high gene marking in long-term self-renewing hematopoietic stem cells (HSCs), preserving their repopulation potential during in vitro manipulation. In the context of the...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050123001705 |
| _version_ | 1827787296597868544 |
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| author | Valentina Poletti Annita Montepeloso Danilo Pellin Alessandra Biffi |
| author_facet | Valentina Poletti Annita Montepeloso Danilo Pellin Alessandra Biffi |
| author_sort | Valentina Poletti |
| collection | DOAJ |
| description | Ex vivo gene therapy (GT) is a promising treatment for inherited genetic diseases. An ideal transduction protocol should determine high gene marking in long-term self-renewing hematopoietic stem cells (HSCs), preserving their repopulation potential during in vitro manipulation. In the context of the improvement of a clinically applicable transduction protocol, we tested prostaglandin E2 (PGE2) as a transduction enhancer (TE). The addition of PGE2 shortly before transduction of human CD34+ cells determined a significant transduction increase in the in vitro cell progeny paralleled by a significant reduction of their clonogenic potential. This effect increased with the duration of PGE2 exposure and correlated with an increase of CXCR4 expression. Blockage of CXCR4 with AMD3100 (plerixafor, Mozobil) did not affect transduction efficiency but partially rescued CD34+ clonogenic impairment in vitro. Once transplanted in vivo in a competitive repopulation assay, human CD34+ cells transduced with PGE2 contributed significantly less than cells transduced with a standard protocol to the repopulation of recipient mice, indicating a relative repopulation disadvantage of the PGE2-treated CD34+ cells and a counter-selection for the PGE2-treated cell progeny in vivo. In conclusion, our data indicate the need for risk/benefit evaluations in the use of PGE2 as a TE for clinical protocols of GT. |
| first_indexed | 2024-03-11T16:47:24Z |
| format | Article |
| id | doaj.art-9c5bfeb7143b470b8f0165885ba64a5d |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-03-11T16:47:24Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-9c5bfeb7143b470b8f0165885ba64a5d2023-10-22T04:49:14ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-12-0131101131Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cellsValentina Poletti0Annita Montepeloso1Danilo Pellin2Alessandra Biffi3Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman’s and Child Health Department, University of Padova, 35128 Padova, Italy; Gene Therapy Program, Boston Children’s Dana-Farber Cancer and Blood Disorder Center, Boston, MA 02115, USA; Corresponding author: Valentina Poletti, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman’s and Child Health Department, University of Padova, 35128 Padova, Italy.Gene Therapy Program, Boston Children’s Dana-Farber Cancer and Blood Disorder Center, Boston, MA 02115, USAGene Therapy Program, Boston Children’s Dana-Farber Cancer and Blood Disorder Center, Boston, MA 02115, USADivision of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman’s and Child Health Department, University of Padova, 35128 Padova, Italy; Gene Therapy Program, Boston Children’s Dana-Farber Cancer and Blood Disorder Center, Boston, MA 02115, USA; Corresponding author: Alessandra Biffi, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman’s and Child Health Department, University of Padova, 35128 Padova, Italy.Ex vivo gene therapy (GT) is a promising treatment for inherited genetic diseases. An ideal transduction protocol should determine high gene marking in long-term self-renewing hematopoietic stem cells (HSCs), preserving their repopulation potential during in vitro manipulation. In the context of the improvement of a clinically applicable transduction protocol, we tested prostaglandin E2 (PGE2) as a transduction enhancer (TE). The addition of PGE2 shortly before transduction of human CD34+ cells determined a significant transduction increase in the in vitro cell progeny paralleled by a significant reduction of their clonogenic potential. This effect increased with the duration of PGE2 exposure and correlated with an increase of CXCR4 expression. Blockage of CXCR4 with AMD3100 (plerixafor, Mozobil) did not affect transduction efficiency but partially rescued CD34+ clonogenic impairment in vitro. Once transplanted in vivo in a competitive repopulation assay, human CD34+ cells transduced with PGE2 contributed significantly less than cells transduced with a standard protocol to the repopulation of recipient mice, indicating a relative repopulation disadvantage of the PGE2-treated CD34+ cells and a counter-selection for the PGE2-treated cell progeny in vivo. In conclusion, our data indicate the need for risk/benefit evaluations in the use of PGE2 as a TE for clinical protocols of GT.http://www.sciencedirect.com/science/article/pii/S2329050123001705gene therapytransduction enhancerlentiviral vectorprostaglandin E2HSPCs |
| spellingShingle | Valentina Poletti Annita Montepeloso Danilo Pellin Alessandra Biffi Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells Molecular Therapy: Methods & Clinical Development gene therapy transduction enhancer lentiviral vector prostaglandin E2 HSPCs |
| title | Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells |
| title_full | Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells |
| title_fullStr | Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells |
| title_full_unstemmed | Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells |
| title_short | Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells |
| title_sort | prostaglandin e2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells |
| topic | gene therapy transduction enhancer lentiviral vector prostaglandin E2 HSPCs |
| url | http://www.sciencedirect.com/science/article/pii/S2329050123001705 |
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