ABSTRACT
Inherited bone marrow failure syndromes (IBMFS) represent a heterogeneous group of multisystem disorders that typically present with cytopenia in early childhood. Efforts to understand the underlying hematopoietic stem cell (HSC) losses have generally focused on postnatal hematopoiesis. However, reflecting the role of many of the involved genes in core cellular functions and the diverse nonhematologic abnormalities seen in patients at birth, studies have begun to explore IBMFS manifestations during fetal development. Here, I consider the current evidence for fetal deficits in the HSC pool and highlight emerging concepts regarding the origins and unique pathophysiology of hematopoietic failure in IBMFS.
Subject(s)
Anemia, Aplastic/embryology , Anemia, Aplastic/physiopathology , Bone Marrow Diseases/embryology , Bone Marrow Diseases/physiopathology , Fetal Development , Genetic Diseases, Inborn/embryology , Genetic Diseases, Inborn/physiopathology , Hematopoiesis , Hemoglobinuria, Paroxysmal/embryology , Hemoglobinuria, Paroxysmal/physiopathology , Anemia, Aplastic/genetics , Animals , Bone Marrow Diseases/genetics , Bone Marrow Failure Disorders , Genetic Diseases, Inborn/genetics , Hemoglobinuria, Paroxysmal/genetics , Humans , Mice , ZebrafishABSTRACT
Pigs share many physiological, biochemical, and anatomical similarities with humans and have emerged as valuable large animal models for biomedical research. Considering the advantages in immune system resemblance, suitable size, and longevity for clinical practical and monitoring purpose, SCID pigs bearing dysfunctional RAG could serve as important experimental tools for regenerative medicine, allograft and xenograft transplantation, and reconstitution experiments related to the immune system. In this study, we report the generation and phenotypic characterization of RAG1 and RAG2 knockout pigs using transcription activator-like effector nucleases. Porcine fetal fibroblasts were genetically engineered using transcription activator-like effector nucleases and then used to provide donor nuclei for somatic cell nuclear transfer. We obtained 27 live cloned piglets; among these piglets, 9 were targeted with biallelic mutations in RAG1, 3 were targeted with biallelic mutations in RAG2, and 10 were targeted with a monoallelic mutation in RAG2. Piglets with biallelic mutations in either RAG1 or RAG2 exhibited hypoplasia of immune organs, failed to perform V(D)J rearrangement, and lost mature B and T cells. These immunodeficient RAG1/2 knockout pigs are promising tools for biomedical and translational research.
Subject(s)
DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Gene Knockout Techniques/methods , Gene Targeting/methods , Homeodomain Proteins/genetics , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/immunology , Anemia, Aplastic/embryology , Anemia, Aplastic/genetics , Anemia, Aplastic/immunology , Animals , Disease Models, Animal , Embryo Transfer , Female , Fibroblasts/immunology , Fibroblasts/pathology , INDEL Mutation , Male , Primary Cell Culture , Recombination, Genetic/immunology , Severe Combined Immunodeficiency/embryology , Sus scrofa , Swine , Swine, MiniatureABSTRACT
Fetal hydrops developed in the 8-day interval between two ultrasonographic examinations of a pregnant woman who had presented with a revealed placental abruption. Chronic ulcerative colitis had been treated with oral prednisone and sulfasalazine until the second month of pregnancy and then with prednisone only. An autolysed hydropic fetus was delivered at 26 weeks gestation. No hematopoietic tissue was identified in the small pale fetal liver, in the bone marrow, or in other organs. No cause for hydrops other than the aplastic anemia was identified.
