Altered erythro-myeloid progenitor cells are highly expanded in intensively regenerating hematopoiesis.
K. Faltusová, C-L. Chen , T. Heizer, M. Báječný, K. Szikszai, P. Páral, F. Savvulidi, N. Renešová and E.Necas (2020), Front. Cell Dev. Biol. doi: 10.3389/fcell.2020.00098
Abstract:
Regeneration of severely damaged adult tissues is currently onlypartially understood. Hematopoietic tissue provides a uniqueopportunity to study tissue regeneration due to its well establishedsteady-state structure and function, easy accessibility, wellestablished research methods, and the well-defined embryonic,fetal, and adult stages of development. Embryonic/fetal liverhematopoiesis and adult hematopoiesis recovering from damageshare the need to expand populations of progenitors and stem cellsin parallel with increasing production of mature blood cells. In thepresent study, we analyzed adult hematopoiesis in mice subjected toa submyeloablative dose (6 Gy) of gamma radiation and targeted theperiod of regeneration characterized by massive production ofmature blood cells along with ongoing expansion of immaturehematopoietic cells. We uncovered significantly expandedpopulations of developmentally advanced erythroid and myeloidprogenitors with significantly altered immunophenotype. Theirpopulation expansion does not require erythropoietin stimulationbut requires the SCF/c-Kit receptor signaling. Regeneratinghematopoiesis significantly differs from the expandinghematopoiesis in the fetal liver but we find some similaritiesbetween the regenerating hematopoiesis and the early embryonicdefinitive hematopoiesis. These are in 1) the concomitant populationexpansion of myeloid progenitors and increasing production ofmyeloid blood cells 2) performing these tasks despite the severelyreduced transplantation capacity of the hematopoietic tissues and 3)the expression of CD16/32 in most progenitors. Our data thusprovide a novel insight into tissue regeneration by suggesting thatcells other than stem cells and multipotent progenitors can be offundamental importance for the rapid recovery of tissue function.
Regenerating haematopoiesis resembles embryonic stem cell-independent haematopoiesis. [in czech only]
E.Nečas, K. Faltusová, (2020), Transfuze Hematol. dnes, Online only, p. 1-15. ISSN 1805-4587
Abstract:
Tissue regeneration is a complex and highly orchestrated process leading to the reconstitution of damaged tissue and recovery of its function. Haematopoietic tissue has extensive regenerative potential which is attributed to the presence of haematopoietic stem cells. This paper briefly discusses the current understanding of haematopoietic stem cells and their participation in steady-state haematopoiesis. It also gives an overview of the three phases of embryonic and foetal haematopoiesis preceding the establishment of steady-state adult haematopoiesis. The paper presents the main conclusions drawn from our analysis of intensively regenerating bone marrow following severe damage by ionizing radiation. The research revealed a fundamental role that the developmentally advanced myeloid progenitor cells play in bone marrow regeneration, which occurs during the virtual absence of stem cells and multipotent progenitors. The regeneration induced by progenitors explains why the strong regenerative power of this tissue cannot be transplanted to other subjects with damaged haematopoiesis. A comparison of the rapidly expanding regenerating bone marrow with the expanding foetal liver haematopoiesis showed significant differences between them. However, there is a similarity between intensively regenerating haematopoiesis and embryonic definitive haematopoiesis occurring prior to the emergence of haematopoietic stem cells.
T-lymphopoiesis is Severely Compromised in Ubiquitin-Green Fluorescent Protein Transgenic Mice
K. Faltusová, M. Báječný, T. Heizer, P. Páral, E. Nečas (2020), FOLIA BIOL (PRAHA). vol. 66, no. 2, p 47-59 ISSN: 0015-5500.
Abstract:
Tagging cells of experimental organisms with genetic markers is commonly used in biomedical research. Insertion of artificial gene constructs can be highly beneficial for research as long as this tagging is functionally neutral and does not alter the tissue function. The transgenic UBC-GFP mouse has been recently found to be questionable in this respect, due to a latent stem cell defect compromising its lymphopoiesis and significantly influencing the results of competitive transplantation assays. In this study, we show that the stem cell defect present in UBC-GFP mice negatively affects T-lymphopoiesis significantly more than B-lymphopoiesis. The production of granulocytes is not negatively affected. The defect in T-lymphopoiesis causes a low total mber of white blood cells in the peripheral blood of UBC-GFP mice which, together with the lower lymphoid/myeloid ratio in nucleated blood cells, is the only abnormal phenotype in untreated UBC-GFP mice to have been found to date. The defective lymphopoiesis in UBC-GFP mice can be repaired by transplantation of congenic wild-type bone marrow cells, which then compensate for the insufficient production of T cells. Interestingly, the wild-type branch of haematopoiesis in chimaeric UBC-GFP/wild-type mice was more active in lymphopoiesis, and particularly towards production of T cells, compared to the lymphopoiesis in normal wild-type donors.
Current understanding of the haematopoietic tissue. [PDF in czech only]
E.Necas, K. Faltusová, (2019), Československá fyziologie vol. 68 no.2, str. 57 - 67, ISSN: 1210 - 6313
Abstract:
Haematopoietic tissue carries out the life long production of blood cells. The quantitative and qualitative aspects of blood cell production are summarised in this short review. The haematopoietic tissue is the best researched tissues regarding the role of stem and progenitor cells in tissue homeostasis and function. Advanced experimental methods, especially cell transplantation and flow cytometry, enable research into the functional organisation of haematopoietic tissue beyond the limits present in other tissues. The review focuses upon the haematopoietic stem cell, the developmental hierarchy in blood cell formation and the role of stroma in the support and control of blood cell production. A brief overview of embryonic and foetal haematopoiesis is also provided.
Stem Cell Defect in Ubiquitin-Green Fluorescent Protein Mice Facilitates Engraftment of Lymphoid-Primed Hematopoietic Stem Cells.
Faltusová, K., Szikszai, K., Molík, M., Linhartová, J., Páral, P., Šefc, L., Savvulidi, F. and Nečas, E. (2018), STEM CELLS. doi: 0.1002/stem.2828.
 Abstract:Transgenic mice expressing green fluorescent protein (GFP) are useful in transplantation experiments. When we used ubiquitin-GFP (UBC-GFP) transgenic mice to study the availability of niches for transplanted hematopoietic stem and progenitor cells, the results were strikingly different from the corresponding experiments that used congenic mice polymorphic in the CD45 antigen. Analysis of these unexpected results revealed that the hematopoiesis of UBC-GFP mice was outcompeted by the hematopoiesis of wild-type (WT) mice. Importantly, UBC-GFP mice engrafted the transplanted bone marrow of WT mice without conditioning. There was a significant bias toward lymphopoiesis in the WT branch of chimeric UBC-GFP/WT hematopoiesis. A fraction of immature Sca-1+ cells in the spleen of UBC-GFP mice expressed GFP at a very high level. The chimeric hematopoiesis was stable in the long term and also after transplantation to secondary recipient mice. The article thus identifies a specific defect in the hematopoiesis of UBC-GFP transgenic mice that compromises the lymphoid-primed hematopoietic stem cells in the bone marrow and spleen. |
Hematopoiesis Remains Permissive to Bone Marrow Transplantation After Expansion of Progenitors and Resumption of Blood Cell Production.
Báječný, M., Chen C.-L.,Faltusová, K., Heizer T., Sziskszai K., Páral P., Šefc, L., and Nečas, E. (2021)., Front. Cell Dev. Biol., https://doi.org/10.3389/fcell.2021.660617
Cell cycle and differentiation of Sca-1 + and Sca-1 − hematopoietic stem and progenitor cells.
Páral, P., Faltusová, K., Molík, M., Renešová, N., Šefc, L., and Nečas, E. (2018)., Cell Cycle 17, 1979–1991. doi:10.1080/15384101.2018.1502573
Low c-Kit Expression Level Induced by Stem Cell Factor Does Not Compromise Transplantation of Hematopoietic Stem Cells.
Chen C-L, Faltusova K, Molik M, Savvulidi F, Chang K-T, Necas E. Biol Blood Marrow Transplant 2016, 22:1167–1172.
Hematopoietic stem cells survive circulation arrest and reconstitute hematopoiesis in myeloablated mice.
Michalova J, Savvulidi F, Sefc L, Faltusova K, Forgacova K, Necas E: Biol Blood Marrow Transplant 2011, 17:1273–81.