Abstract
The bone marrow niche plays critical roles in hematopoietic recovery and hematopoietic stem cell (HSC) regeneration after myeloablative stress. However, it is not clear whether systemic factors beyond the local niche are required for these essential processes in vivo. Thrombopoietin (THPO) is a key cytokine promoting hematopoietic rebound after myeloablation and its transcripts are expressed by multiple cellular sources. The upregulation of bone marrow-derived THPO has been proposed to be crucial for hematopoietic recovery and HSC regeneration after stress. Nonetheless, the cellular source of THPO in myeloablative stress has never been investigated genetically. We assessed the functional sources of THPO following two common myeloablative perturbations: 5-fluorouracil (5-FU) administration and irradiation. Using a Thpo translational reporter, we found that the liver but not the bone marrow is the major source of THPO protein after myeloablation. Mice with conditional Thpo deletion from osteoblasts and/or bone marrow stromal cells showed normal recovery of HSCs and hematopoiesis after myeloablation. In contrast, mice with conditional Thpo deletion from hepatocytes showed significant defects in HSC regeneration and hematopoietic rebound after myeloablation. Thus, systemic THPO from the liver is necessary for HSC regeneration and hematopoietic recovery in myeloablative stress conditions.
Highlights
Hematopoietic stem cells (HSCs) generate all blood and immune cells, and play critical roles in the regeneration of the blood system after stress
When normalized to baseline levels, Thpogfp/gfp mice had a significant reduction of leukocyte, neutrophil, and platelet counts as well as reticulocyte frequency compared with wild-type controls (Figure 1-figure supplement 1 A-H), suggesting that Thpo is required for hematopoietic recovery
We did not exhaustively investigate all models of ablative conditioning, it appears that the bone marrow is not a functional source of THPO in hematopoietic recovery from acute myeloablative stress
Summary
Hematopoietic stem cells (HSCs) generate all blood and immune cells, and play critical roles in the regeneration of the blood system after stress They reside in the bone marrow niche where. Many of the secreted cytokines activating these pathways arise from the local bone marrow niche and regulate HSC regeneration and hematopoietic recovery in a paracrine fashion (Guo et al, 2017; Himburg et al, 2017; Poulos et al, 2013; Zhou et al, 2017). Most studies proposed that local THPO derived from the bone marrow niche is critical for HSC and hematopoietic recovery after myeloablation (Kaushansky, 2005; Yoshihara et al, 2007). We genetically dissected the in vivo source of THPO for HSC and hematopoietic recovery following myeloablative stress
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