Purinergic signaling in bone marrow stem cell mobilization

The paper by Cymer et al., “Pannexin-1 channel fuels by releasing ATP from bone marrow cells, a state of sterile inflammation required for optimal mobilization and homing of hematopoietic stem cells,” which is published in this issue of Purinergic Signalling, describes a novel method of sterile inflammation in stem cell mobilization. Interestingly, this study describes a dual role for pannexin-1, namely stem cell egress from bone marrow and homing into this organ. This double role for pannexin-1 channel makes this study novel because in general, a mobilizing agent moves cells from bone marrow into the periphery, but not the opposite. The authors used two known mobilizing agents, granulocyte-colony stimulating factor (G-CSF) and a CXCR4 inhibitor (AMD3100), to prove their main findings as the basis for their model system.

Pannexin -1 forms small channels and is mostly linked to neurones, allowing for passage of ions and metabolites (1). Pannexin-1, through the release of ATP from bone marrow innate immune cells, establishes a sterile inflammatory environment to regulate the mobilization of HSC and other resident stem cells, including Mesenchymal stem cells (MSCs), endothelial progenitors, and very small embryonic-like (VSEL) stem cells. Pannexin-1 releases extracellular ATP (eATP) to induce a sterile inflammatory environment.

Sterile inflammation, although carrying hallmarks of an infection, occurs independently of an infection, which may occur via the induction of danger-associated molecular patterns (DAMPs). This study also showed the release of mitochondrial DNA, which could also lead to sterile infection. Together, the findings underscore a complex mechanism of pannexin-1 function in stem cell mobilization. The dual roles for pannexin-1 are mediated by eATP. Interestingly, the two HSC mobilization agents, G-CSF and AMD3100, induce eATP, strongly suggesting that this could be an unknown mechanism of these agents, not previously reported. The role for pannexin-1 was demonstrated indirectly with a small molecule inhibitor that inhibits the release of eATP. Ideally, this study requires molecular knockdown of pannexin-1 to determine if its mechanisms is redundant to related channels. Nonetheless, these findings, combined with the identification of inflammasome mediators, underscore the importance of sterile inflammation in harvesting bone marrow cells as well as to during transplant.

The clinical relevance for this study is the contribution to the future of stem cell transplantation. HSC transplantation, has for many decades, utilized G-CSF to mobilize hematopoietic cell into the periphery, termed mobilized peripheral blood stem cells (MPB). Several days after injection of G-CSF, the stem cells are collected for transplantation to replace the human hematopoietic system. The method has been used successfully to treat leukemia and other hematological disorders. Transplant for solid tumors is less common, although there are documented case of HSC transplant for these cancers.

Interestingly, G-CSF and AMD3100 were not previously linked to sterile inflammation. G-CSF and AMD3100 increased inflammasome mediators and these appeared to be from cells of the innate immune system, mostly neutrophils and monocytes. Individuals and patients in the realm of transplant should take this study seriously. In general, the number of days used to administer G-CSF depends on the recipient. If there is enormous induction of inflammasome activity, with activation of the innate immune system, the question is how does this affect the harvested cells?

A caveat of this study is the lack of information on other bone marrow cells with regard to sterile inflammation. It is possible that data are available for other cell types, but are not included in this publication. Cells of the bone marrow microenvironment are of particular interest because they support hematopoiesis and are important for sequestration of stem cells in the organ. Other mechanisms have been reported for G-CSF and AMD3100, but the involvement of pannexin-1 in a critical step during mobilization is new. This study could have a tremendous benefit to public health because the bone marrow is the site of immune cell formation. If sterile inflammation could be activated by other bone marrow cells, this could perhaps explain several clinical observations, such as surgical trauma.

The authors demonstrated pannexin-1-mediated mobilization of MSCs (2). It is unclear how MSCs, which are important in regulating an inflammatory microenvironment, would affect the stem cell mobilization by pannexin-1. Indeed, the authors showed MSCs as those being mobilized by pannexin-1. If MSCs leave the bone marrow to regulate danger in the periphery, this might explain why they cannot regulate the inflammation within bone marrow. However, this could be an advantage because, based on this publication, sterile inflammation is required to mobilize hematopoietic stem and progenitor cells out of the bone marrow. Going forward, it is important to dissect the roles of these and other bone marrow cells.

An important point is to consider is that bone marrow is innervated. Peptides emanating from these nerve endings can regulate hematopoiesis (3). Thus, it is important to examine the neural system in bone marrow to fundamentally dissect pannexin-1-mediated sterile inflammation (1). A major question from this study is whether there is movement of HSCs back and forth in the bone marrow. This question is relevant because 10% of donors do not appear to harvest at the optimal level. If the scientific community determine that this is accurate or is due to the loss of HSCs, which return to the bone marrow, there should be additional experimental studies to determine how pannexin-1 small molecule inhibitors may be used with other mobilizing agents to achieve optimum stem cell harvest.

Compliance with ethical standards

Conflicts of interest

Pranela Rameshwar declares that she has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.