Potential long-term treatment of hemophilia A by neonatal co-transplantation of cord blood-derived endothelial colony-forming cells and placental mesenchymal stromal cells

Autor: Jan A. Nolta, Ping Zhou, Jianda Zhou, Chuwang Wang, Lizette Reynaga, Diana L. Farmer, Aijun Wang, Priyadarsini Kumar, Elizabeth Cortez-Toledo, Dake Hao, Kewa Gao, Melanie Rose
Rok vydání: 2019
Předmět:
Co-transplantation
0301 basic medicine
Technology
Placenta
Genetic enhancement
Cell
Mesenchymal stromal cells
Stem Cell Research - Umbilical Cord Blood/ Placenta - Human
Medicine (miscellaneous)
Regenerative Medicine
Factor FVIII
Medical and Health Sciences
Mice
0302 clinical medicine
Stem Cell Research - Nonembryonic - Human
Pregnancy
Neonatal
lcsh:QD415-436
Pediatric
lcsh:R5-920
Endothelial colony-forming cells
Hematology
Gene Therapy
Biological Sciences
Fetal Blood
surgical procedures
operative
medicine.anatomical_structure
030220 oncology & carcinogenesis
Cord blood
Molecular Medicine
Stem Cell Research - Nonembryonic - Non-Human
Female
Development of treatments and therapeutic interventions
Stem cell
lcsh:Medicine (General)
Cell engraftment
Biotechnology
Stem Cell Research - Umbilical Cord Blood/ Placenta
Mesenchymal stromal cells (MSCs)
Cell Engraftment
Hemophilia A
Biochemistry
Genetics and Molecular Biology (miscellaneous)
Viral vector
lcsh:Biochemistry
Endothelial colony-forming cells (ECFCs)
03 medical and health sciences
Rare Diseases
Cotransplantation
In vivo
Genetics
medicine
Animals
Humans
Bioluminescence imaging
Transplantation
5.2 Cellular and gene therapies
business.industry
Research
Mesenchymal stem cell
Infant
Newborn
Infant
Endothelial Cells
Mesenchymal Stem Cells
Cell Biology
Newborn
Stem Cell Research
030104 developmental biology
Cancer research
business
Zdroj: Stem Cell Research & Therapy
Stem cell research & therapy, vol 10, iss 1
Stem Cell Research & Therapy, Vol 10, Iss 1, Pp 1-15 (2019)
ISSN: 1757-6512
Popis: Background Hemophilia A (HA) is an X-linked recessive disorder caused by mutations in the Factor VIII (FVIII) gene leading to deficient blood coagulation. As a monogenic disorder, HA is an ideal target for cell-based gene therapy, but successful treatment has been hampered by insufficient engraftment of potential therapeutic cells. Methods In this study, we sought to determine whether co-transplantation of endothelial colony-forming cells (ECFCs) and placenta-derived mesenchymal stromal cells (PMSCs) can achieve long-term engraftment and FVIII expression. ECFCs and PMSCs were transduced with a B domain deleted factor VIII (BDD-FVIII) expressing lentiviral vector and luciferase, green fluorescent protein or Td-Tomato containing lentiviral tracking vectors. They were transplanted intramuscularly into neonatal or adult immunodeficient mice. Results In vivo bioluminescence imaging showed that the ECFC only and the co-transplantation groups but not the PMSCs only group achieved long-term engraftment for at least 26 weeks, and the co-transplantation group showed a higher engraftment than the ECFC only group at 16 and 20 weeks post-transplantation. In addition, cell transplantation at the neonatal age achieved higher engraftment than at the adult age. Immunohistochemical analyses further showed that the engrafted ECFCs expressed FVIII, maintained endothelial phenotype, and generated functional vasculature. Next, co-transplantation of ECFCs and PMSCs into F8 knock-out HA mice reduced the blood loss volume from 562.13 ± 19.84 μl to 155.78 ± 44.93 μl in a tail-clip assay. Conclusions This work demonstrated that co-transplantation of ECFCs with PMSCs at the neonatal age is a potential strategy to achieve stable, long-term engraftment, and thus holds great promise for cell-based treatment of HA. Electronic supplementary material The online version of this article (10.1186/s13287-019-1138-8) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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