The global clonal complexity of the murine blood system declines throughout life and after serial transplantation
| Autor: | David Finkelstein, Ashley Chabot, Guolian Kang, Shannon McKinney-Freeman, Miguel Ganuza, Wenjian Bi, Trent Hall, Gang Wu, Yong-Dong Wang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Immunology Plenary Paper Hematopoietic stem cell transplantation Biology medicine.disease_cause Biochemistry 03 medical and health sciences Mice 0302 clinical medicine Life medicine Animals Mutation Serial Transplantation Hematopoietic Stem Cell Transplantation Cell Biology Hematology Hematopoietic Stem Cells Transplantation Haematopoiesis 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Bone marrow Stem cell Ex vivo |
| Zdroj: | Blood |
| Popis: | Although many recent studies describe the emergence and prevalence of “clonal hematopoiesis of indeterminate potential” in aged human populations, a systematic analysis of the numbers of clones supporting steady-state hematopoiesis throughout mammalian life is lacking. Previous efforts relied on transplantation of “barcoded” hematopoietic stem cells (HSCs) to track the contribution of HSC clones to reconstituted blood. However, ex vivo manipulation and transplantation alter HSC function and thus may not reflect the biology of steady-state hematopoiesis. Using a noninvasive in vivo color-labeling system, we report the first comprehensive analysis of the changing global clonal complexity of steady-state hematopoiesis during the natural murine lifespan. We observed that the number of clones (ie, clonal complexity) supporting the major blood and bone marrow hematopoietic compartments decline with age by ∼30% and ∼60%, respectively. Aging dramatically reduced HSC in vivo–repopulating activity and lymphoid potential while increasing functional heterogeneity. Continuous challenge of the hematopoietic system by serial transplantation provoked the clonal collapse of both young and aged hematopoietic systems. Whole-exome sequencing of serially transplanted aged and young hematopoietic clones confirmed oligoclonal hematopoiesis and revealed mutations in at least 27 genes, including nonsense, missense, and deletion mutations in Bcl11b, Hist1h2ac, Npy2r, Notch3, Ptprr, and Top2b. |
| Databáze: | OpenAIRE |
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