Kateřina Faltusová PhD thesis

The role of stem and progenitor cells in regeneration of hematopoietic tissue
Prague, 2021

Abstract:
Tissue regeneration is a complex and highly orchestrated process dependent on cells with the potential to restore structures and functions and on controlling factors from the tissue microenvironment. Hematopoietic tissue has a high ability to regenerate, which is attributed to the presence of stem cells, but the regeneration of severely damaged adult tissue is still 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, advanced research methods, and 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.
We analyzed adult hematopoiesis in mice subjected to a submyeloablative dose (6 Gy) of gamma radiation, in which only a few cells with reconstituting capacity survived. We targeted the period of regeneration characterized by the renewed massive production of mature blood cells and the ongoing expansion of immature hematopoietic cells. Cells from the top of the hematopoietic hierarchy, hematopoietic stem cells, and multipotent progenitors are almost missing in this period of hematopoiesis regeneration. We uncovered significantly expanded populations of developmentally advanced erythroid and myeloid progenitors with significantly altered immunophenotype and with the ability for intensive proliferation. These immature hematopoietic cells differ from the progenitor cells present in normal bone marrow by the decreased expression level of the c-Kit receptor for stem cell factor, the expression of Sca-1 antigen also in the cells which express transferrin receptor 1 (CD71), by expression of CD16/32 in most of the cells, and by altered expression of CD41. These progenitors activated the erythroid developmental program independently from erythropoietin production. Despite decreased expression of the c-Kit receptor, progenitors require effective stimulation by stem cell factor (SCF) for their expansion.
Hematopoietic stem cells, defined by their ability to reconstitute destroyed hematopoiesis in the host, were reduced to 1 – 2 % of their normal number in the intensively regenerating hematopoiesis.
It was shown that the early reconstitution of hematopoiesis from transplanted cells that were not exposed to radiation gives rise to populations of altered progenitors, which are similar to those identified in the bone marrow regenerating from endogenous cells surviving exposure to ionizing radiation.
Regenerating hematopoiesis differs significantly from the expanding hematopoiesis in the fetal liver by the virtual lack of stem cells and different immunophenotypes of progenitor cells
The data presented in this study 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, and the regenerating adult hematopoiesis shares some features with the embryonic hematopoiesis preceding the development of stem cells.