A new look at the role of complement circulating in peripheral blood and expressed in hematopoietic stem cells in the regulation of hematopoiesis

Hematopoietic transplantation is performed by intravenous infusion of donor-derived or autologous hematopoietic stem progenitor cells (HSPCs), which, in response to bone marrow (BM)-expressed chemoattractant navigate and home to BM hematopoietic niches. This process is followed by their engraftment and expansion to repopulate the recipient’s BM myeloablated before transplantation. The most important BM chemoattractant is the alpha-chemokine stromal-derived factor 1 (SDF-1). However, its homing role is supported by the bioactive phosphospingolipid sphingosine-1-phosphate (S1P) and by extracellular adenosine triphosphate (eATP). As we demonstrated in the past, the CXCR4 receptor for SDF-1 must be incorporated into cell surface membrane lipid rafts (MLRs) for optimal SDF-1 gradient sensing by HSPCs. Our previous research demonstrated that an important and for many years underestimated role in hematopoiesis plays an innate immunity soluble arm that is complement cascade (ComC). We provided an evidence that ComC becomes activated in BM during pharmacological mobilization in response to granulocyte colony-stimulating factor (G-CSF) or CXCR4 receptor antagonist AMD3100. In this proposal, we will focus on the role of ComC in a reverse phenomenon that is posttransplant homing/engraftment of HSPCs. It is known that the critical step before infusion of HSPCs is the myeloablative treatment of the recipient aimed to destroy pathological hematopoiesis and empty BM niches to provide space available for new transplanted HSPCs. Myeloablative treatment involves high-dose chemotherapy or myeloablative irradiation. In experimental animal transplant models, lethal irradiation is a standard procedure. The available literature indicates that both irradiation and chemotherapy induce in various organs and tissues similarly as during mobilization a state of sterile inflammation and extracellular ATP (eATP) released from damaged cells triggers this process. We postulate that the same occurs in the BM microenvironment, and in fact, our preliminary data shows that ComC becomes activated in mice after myeloablative conditioning for transplantation by lethal gamma-irradiation or exposure to myeloablative chemotherapy. It is known that ComC could be activated by i) classical-, ii) mannan-binding lectin, or iii) alternative-pathway. Activation of ComC leads to the release C3 and C5 complement components cleavage fragments - C3a and C5a anaphylatoxins that are processed by serum carboxypeptidase to desArgC3a and desArgC5a as well as leads to the formation of C5b-C9 or non-lytic or lytic membrane attack complex (MAC), which is the terminal product of ComC activation. On the other hand, both HSPCs and cells in the BM microenvironment express receptors for C3a and C5a (C3aR, C5aR1, and C5aR2). After myeloablative therapy, active ComC cleavage fragments circulate in PB. Therefore, HSPCs infused into the transplant recipient's bloodstream are exposed to these potent innate immunity mediators. This interaction of HSPCs with ComC meditators, as we propose, promotes better navigation of infused cells to the recipient BM niches and we hypothesize is a result of the promotion of MLRs formation on HSPCs. On the other hand, myeloablative conditioning for transplantation induces a state of sterile inflammation in transplant recipient BM to facilitate homing and engraftment of circulating in PB transplanted HSPCs. Finally, new intriguing evidence accumulated that in addition to the liver ComC synthesis occurs also inside some cells – e.g., in lymphocytes. Our recent data indicate that the same phenomenon occurs in HSPCs. Therefore, the intercellular expression of ComC elements known as complosome sheds new light on the underappreciated role of innate immunity in regulating hematopoiesis.

This work was supported by the National Science Centre, Poland OPUS grant UMO-2022/45/B/NZ6/00475. 

The data included in the database were used in the following publications:

1. https://www.nature.com/articles/s41375-024-02188-9

2. https://link.springer.com/article/10.1007/s11302-023-09943-0

3. https://www.nature.com/articles/s41375-023-01894-0