A human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells.
Blood
; 135(19): 1661-1672, 2020 05 07.
Article
em En
| MEDLINE
| ID: mdl-32206775
ABSTRACT
In human-to-mouse xenogeneic transplantation, polymorphisms of signal-regulatory protein α (SIRPA) that decide their binding affinity for human CD47 are critical for engraftment efficiency of human cells. In this study, we generated a new C57BL/6.Rag2nullIl2rgnull (BRG) mouse line with Sirpahuman/human (BRGShuman) mice, in which mouse Sirpa was replaced by human SIRPA encompassing all 8 exons. Macrophages from C57BL/6 mice harboring Sirpahuman/human had a significantly stronger affinity for human CD47 than those harboring SirpaNOD/NOD and did not show detectable phagocytosis against human hematopoietic stem cells. In turn, Sirpahuman/human macrophages had a moderate affinity for mouse CD47, and BRGShuman mice did not exhibit the blood cytopenia that was seen in Sirpa-/- mice. In human to mouse xenograft experiments, BRGShuman mice showed significantly greater engraftment and maintenance of human hematopoiesis with a high level of myeloid reconstitution, as well as improved reconstitution in peripheral tissues, compared with BRG mice harboring SirpaNOD/NOD (BRGSNOD). BRGShuman mice also showed significantly enhanced engraftment and growth of acute myeloid leukemia and subcutaneously transplanted human colon cancer cells compared with BRGSNOD mice. BRGShuman mice should be a useful basic line for establishing a more authentic xenotransplantation model to study normal and malignant human stem cells.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fagocitose
/
Células-Tronco Neoplásicas
/
Células-Tronco Hematopoéticas
/
Receptores Imunológicos
/
Leucemia Mieloide Aguda
/
Antígenos de Diferenciação
/
Neoplasias do Colo
/
Hematopoese
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Blood
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Japão