Page 54 - Haematologica May 2020

H. Li et al.
higher expressed in adult steady-state BMSC compared with fetal BMSC and BMSC in regenerating marrow (Figure 1B), both of the latter showing higher prolifera- tion compared to steady-state BMSC. Thus, these data point to a possible key role in vivo of EGR1, regulating the response to the different requirements in development and under pathological conditions. In the fetal period, there is demand for a high proliferation of BMSC with potent osteogenic and stroma differentiation potential. Likewise, primarily cellular regeneration is required after stromal damage, for example, following myelotoxic chemo- or radiotherapy. In addition, murine data demon- strated that BMSC expanded considerably following irra- diation and BM transplantation.22 In contrast, hematopoi- etic support is most important in steady-state adult BM, whereas there is only a limited need for BMSC prolifera- tion. However, whether or not a demand-controlled EGR1 regulation of proliferation and stroma function is operative in vivo has not yet been investigated, but is cer- tainly an interesting and highly relevant topic for future research.
Taken together, we demonstrate that EGR1 is a key dual regulator of human BMSC which controls a genetic program co-ordinating specific functions of BMSC in their different biological contexts. High EGR1 expression induced potent hematopoietic stroma support by expres- sion of high levels of hematopoiesis-supporting genes and suppressed BMSC proliferation, whereas EGR1 downreg- ulation promoted BMSC proliferation at the expense of
hematopoietic support function. These data thus consid- erably expand our current understanding of the regulation of BMSC under distinct physiological and developmental conditions. Furthermore, they have clear implications for the development of stroma replacement and repair strate- gies, for example, for optimizing BMSC expansion proto- cols in vitro and to improve stroma function in transplan- tation patients with poor graft function, as well as stro- ma-mediated HSC expansion approaches.
Funding
This work was supported by funds from the HematoLinné and StemTherapy Program, the Swedish Cancer Foundation, the Swedish Childhood Cancer Foundation, Gunnel Björk’s Testament, Gunda Nilsson’s Testament, the Åke och Inger Bergkvists stiftelse, ALF (Government Public Health Grant), and the Skåne County Council Research Foundation.
Acknowledgments
The authors would like to thank Helene Larsson and Anna Jonasson for their help to collect bone marrow samples and the Lund Stem Cell Center FACS facility personnel for technical assistance. Furthermore, support from the Swedish National Infrastructure for Biological Mass Spectrometry (BioMS) is gratefully acknowledged. We would also like to thank Professors Axel Schambach, Manuel Grez, and Thomas Moritz for pro- viding the A2UCOE-EFS promoter used to generate the lentivector driving expression of EGR1, and Jonas Larsson for crtically reading the manuscript.
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