lentiviral-crisprcas9-mediated-genome-editing-for-study-hematopoietic

Lentiviral CRISPR/Cas9-Mediated Genome Editing for the Study of Hematopoietic Cells in Disease Models

Manipulating genes in hematopoietic stem cells using conventional transgenesis approaches can be time-consuming, expensive, and challenging. Benefiting ...

bone-marrow-transplantation-procedures-mice-to-study-clonal

Bone Marrow Transplantation Procedures in Mice to Study Clonal Hematopoiesis

Clonal hematopoiesis is a prevalent age-associated condition that results from the accumulation of somatic mutations in hematopoietic stem and progenitor ...

University of Virginia School of Medicine

Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We developed a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR2+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac-resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2-mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.

Keita Horitani

Hematovascular Biology Center,
Robert M. Berne Cardiovascular Research Center,
Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center

University of Virginia School of Medicine

Lentiviral CRISPR/Cas9-Mediated Genome Editing for the Study of Hematopoietic Cells in Disease Models

Bone Marrow Transplantation Procedures in Mice to Study Clonal Hematopoiesis

Keita Horitani

Hematovascular Biology Center,Robert M. Berne Cardiovascular Research Center,Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center

University of Virginia School of Medicine

Lentiviral CRISPR/Cas9-Mediated Genome Editing for the Study of Hematopoietic Cells in Disease Models

Bone Marrow Transplantation Procedures in Mice to Study Clonal Hematopoiesis

Hematovascular Biology Center,
Robert M. Berne Cardiovascular Research Center,
Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center