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Abstract
Regeneration of severely damaged adult tissues is currently only partially understood. Hematopoietic tissue provides a unique opportunity to study tissue regeneration due to its well established steady-state structure and function, easy accessibility, well established research methods, and the well-defined embryonic, fetal, and adult stages of development. Embryonic/fetal liver hematopoiesis and adult hematopoiesis recovering from damage share the need to expand populations of progenitors and stem cells in parallel with increasing production of mature blood cells. In the present study, we analyzed adult hematopoiesis in mice subjected to a submyeloablative dose (6 Gy) of gamma radiation and targeted the period of regeneration characterized by massive production of mature blood cells along with ongoing expansion of immature hematopoietic cells. We uncovered significantly expanded populations of developmentally advanced erythroid and myeloid progenitors with significantly altered immunophenotype. Their population expansion does not require erythropoietin stimulation but requires the SCF/c-Kit receptor signaling. Regenerating hematopoiesis significantly differs from the expanding hematopoiesis in the fetal liver but we find some similarities between the regenerating hematopoiesis and the early embryonic definitive hematopoiesis. These are in (1) the concomitant population expansion of myeloid progenitors and increasing production of myeloid blood cells (2) performing these tasks despite the severely reduced transplantation capacity of the hematopoietic tissues, and (3) the expression of CD16/32 in most progenitors. Our data thus provide a novel insight into tissue regeneration by suggesting that cells other than stem cells and multipotent progenitors can be of fundamental importance for the rapid recovery of tissue function.
Highlights
Tissue regeneration is a complex and highly orchestrated process leading to tissue reconstitution and recovery of its function
We show that the regenerating hematopoietic system significantly differs from the expanding hematopoiesis in the fetal liver and early postnatal bone marrow, but find some similarities with the early embryonic definitive hematopoiesis driven by myeloid progenitors before the emergence of transplantable hematopoietic stem cells (HSCs)
To define the experimental model of hematopoietic regeneration used in the present study, we estimated the extent of the initial damage inflicted on the hematopoietic tissue by irradiating mice with a dose of 6 Gy by determining the occurrence of endogenous spleen colonies arising from the myeloid progenitor cells which survived irradiation
Summary
Tissue regeneration is a complex and highly orchestrated process leading to tissue reconstitution and recovery of its function. Several experimental findings have indicated a more complex organization of the immature hematopoietic cells and challenged the idea that the extensive self-renewal capacity is a unique property of HSCs (Adolfsson et al, 2005; England et al, 2011; Yamamoto et al, 2013; Kim et al, 2015). Busch et al (2015) demonstrated that undisturbed adult hematopoiesis is largely sustained by cells downstream of HSCs, and Schoedel et al (2016) reported a long-term hematopoiesis occurring in the absence of HSCs while, in contrast, Sawai et al (2016) and Akinduro et al (2018) presented the data supporting the continuous contribution of HSCs for steady state hematopoiesis. The megakaryocyte-deficient lympho-erythromyeloid progenitors and megakaryocyte-restricted progenitors with the properties of long-term HSC were described in unperturbed adult hematopoiesis (Carrelha et al, 2018; Rodriguez-Fraticelli et al, 2018)
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