|Year : 2022 | Volume
| Issue : 3 | Page : 270-275
Hematopoietic stem cell mobilization
Hsin-Hou Chang, Yu-Shan Liou, Der-Shan Sun
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan
|Date of Submission||13-Apr-2021|
|Date of Decision||28-May-2021|
|Date of Acceptance||25-Jun-2021|
|Date of Web Publication||21-Oct-2021|
Department of Molecular Biology and Human Genetics, Tzu Chi University, 701, Zhongyang Road, Section 3, Hualien
Source of Support: None, Conflict of Interest: None
Hematopoietic stem cell (HSC) transplantation has been used to treat hematopoietic diseases for over 50 years. HSCs can be isolated from bone marrow (BM), umbilical cord blood, or peripheral blood. Because of lower costs, shorter hospitalization, and faster engraftment, peripheral blood has become the predominant source of HSCs for transplantation. The major factors determining the rate of successful HSC transplantation include the degree of human leukocyte antigen matching between the donor and recipient and the number of HSCs for transplantation. Administration of granulocyte colony-stimulating factor (G-CSF) alone or combined with plerixafor (AMD3100) are clinical used methods to promote HSC mobilization from BM to the peripheral blood for HSC transplantations. However, a significant portion of healthy donors or patients may be poor mobilizers of G-CSF, resulting in an insufficient number of HSCs for the transplantation and necessitating alternative strategies to increase the apheresis yield. The detailed mechanisms underlying G-CSF-mediated HSC mobilization remain to be elucidated. This review summarizes the current research on deciphering the mechanism of HSC mobilization.
Keywords: Granulocyte colony-stimulating factor, Hematopoietic stem cell transplantation, Mobilization
|How to cite this article:|
Chang HH, Liou YS, Sun DS. Hematopoietic stem cell mobilization. Tzu Chi Med J 2022;34:270-5
| Introduction|| |
Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche. “Niche” was first proposed as a medical term by Schofield in 1978. The niche comprises various cells that support the microenvironment to prevent stem cell differentiation and maintain self-renewal capabilities. Many cell types in BM, including nonhematopoietic and hematopoietic cells, form the niche network to regulate and retain HSCs in BM,. Autologous or allogeneic HSC transplantation has become a primary treatment for many hematopoietic diseases, such as sickle cell anemia, thalassemia, and hematological malignancies,,,,,,. Sources of HSCs are BM, mobilized peripheral blood, and umbilical cord blood. Because of lower costs, a less invasive harvesting procedure, faster engraftment, higher HSC yields, and shorter hospitalization, mobilized peripheral blood has replaced BM as the routinely used source for HSC transplantation. Successful HSC transplantation requires good matching of the human leukocyte antigen between the donor and recipient and a sufficient number of HSCs. After 4–5 days of treatment with granulocyte colony-stimulating factor (G-CSF), the number of HSCs in the peripheral blood increases by an average of 50–100 times,; thus, G-CSF represents the gold standard agent for mobilized peripheral blood HSC transplantation. Nevertheless, approximately 5%–10% of healthy donors and up to 40% of patients requiring autologous transplant are poor mobilizers of G-CSF,,,,. However, it is challenging to identify such poor mobilizers. To obtain a sufficient number of HSCs for transplantation, alternative strategies (such as larger volume leukapheresis, re-mobilization, the use of other mobilization agents, chemotherapy plus G-CSF, and BM harvesting) can be used. A better understanding of how HSCs are mobilized from BM to peripheral blood can help in developing a more effective regimen for HSC transplantation. In this review, we discuss some known mechanisms of HSC mobilization.
| Proteases released by neutrophils change hematopoietic stem cell retention in bone marrow|| |
On G-CSF administration, neutrophils are activated and degranulated, releasing the serine proteases neutrophil elastase, cathepsin G (CG), dipeptidyl peptidase I (DPPI), and matrix metalloprotease 9. These proteases accumulate in BM and allow for the degradation of molecules (vascular cell adhesion molecule 1 [VCAM-1], stromal-derived factor-1 [SDF-1, also called CXCL12], and c-Kit [CD117]), thus disrupting the interaction with very late antigen-4 (VLA-4), CXC chemokine receptor-4 (CXCR4), and stem cell factor, respectively. This disruption interaction between HSCs and niche cells leads to HSC mobilization,,,,, [Figure 1]a and [Figure 1]b. The mobilization drug plerixafor (AMD3100) has a similar mechanism, plerixafor combined with G-CSF can enhance HSC mobilization by 2–3 times compared with G-CSF alone. Thus, plerixafor serves as a mobilization-enhancing agent when used together with other agents, especially in patients with lymphoma or myeloma who have been heavily pretreated with G-CSF,. Plerixafor binds to CXCR4 expressed on the HSCs, blocks the adhesion between HSCs and niche cells, and then mobilizes HSCs,. Compared with G-CSF, plerixafor-triggered HSC mobilization has clear mechanism. The interaction between Notch2 and its ligand also maintains HSC niche retention; Notch2-blocking antibodies sensitize HSCs to the mobilizing stimuli of G-CSF and plerixafor, resulting in a 3–4-fold increase in mobilization,,.
|Figure 1: Granulocyte colony-stimulating factor stimulates hematopoietic stem cell mobilization by cleaving the retention axes, downregulating stromal-derived factor-1 expression, opening the endothelial boundaries, and counteracting the function of CXC chemokine receptor-4 through erythroblasts-derived fibroblast growth factor 23. In the steady state, hematopoietic stem cells are located and retained in bone marrow through several retention axes, such as SCF/c-kit, vascular cell adhesion molecule 1/VLA-4, and stromal-derived factor-1/CXC chemokine receptor-4 between hematopoietic stem cells and niche cells (a). Upon granulocyte colony-stimulating factor treatment, neutrophils secrete proteases, such as neutrophil elastase, cathepsin G, dipeptidyl peptidase I, and matrix metalloprotease 9, to cleave the retention axes (b). Granulocyte colony-stimulating factor induces sympathetic neurons to secrete noradrenaline and macrophages to secrete unknown factors to suppress stromal-derived factor-1 expression on the surface of niche cells (c). Granulocyte colony-stimulating factor increases CD26 on the surface of endothelial cells and then cleaves the N-terminal of NPY. Truncated NPY then binds the receptors on the surface of endothelial cells, downregulates VE-cadherin, and opens endothelial boundaries (d). Granulocyte colony-stimulating factor triggers erythroblasts to secrete fibroblast growth factor 23 and then counteract the function of CXC chemokine receptor-4 (e).|
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| Reduction of stromal-derived factor-1 expression in niche cells promotes hematopoietic stem cell mobilization|| |
G-CSF activates the sympathetic neurons innervating BM by binding to the G-CSF receptors and then releases noradrenaline to reduce SDF-1 expression (which binds to CXCR4 on the HSCs) on the osteoblasts and nestin+ mesenchymal stem cells through β2-and β3-adrenergic receptors, respectively,,. G-CSF can also activate the macrophages in BM to release some unknown factors to suppress SDF-1 expression on the surface of osteoblasts and then promote HSC mobilization,,,. The SDF-1/CXCR4 axis retains HSCs in BM; downregulation of SDF-1 expression disrupts the retention axis and promotes the exit of HSCs from BM [Figure 1]c.
| Perturbation of the endothelial cell junctions results in increased permeability and hematopoietic stem cell mobilization|| |
Following G-CSF administration, CD26 (also known as dipeptidylpeptidase-4) is increased on the sinusoidal endothelial cells, which become the gatekeepers at BM–peripheral blood interface and regulate hematopoietic cell trafficking. CD26, a serine exopeptidase, cleaves N-terminal dipeptides of the full length of neuropeptide Y (NPY) to form NPY3-36. The truncated NPY preferentially binds to NPYR2 and NPYR5 instead of NPYR1. After binding, the tight junction element vascular endothelial cadherin (VE-cadherin), is internalized and degraded, thus enhancing HSC transendothelial migration, [Figure 1]d.
| Fibroblast growth factor 23 secreted by erythroblasts promotes hematopoietic stem cell mobilization|| |
The hormone fibroblast growth factor 23 (FGF-23), mainly secreted by osteoblasts and osteocytes, regulates phosphate homeostasis in the kidney and suppresses erythropoiesis,. G-CSF can trigger erythroblasts in BM to release FGF-23 within the first 24 h of G-CSF administration. FGF-23 can counteract the function of CXCR4 and then mobilize HSCs, [Figure 1]e.
| Coupling of purinergic signaling, NOD-like receptor family pyrin domain-containing 3 inflammasome, and the complement cascade promotes hematopoietic stem cell mobilization|| |
Accumulated studies have revealed that G-CSF can activate innate immune cells, including granulocytes and monocytes, to release extracellular adenosine triphosphate (eATP) in a pannexin-1 channel-dependent manner,. eATP subsequently activates the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes through P2X4 and P2X7 purinergic receptors on the surface of HSCs or innate immune cells,,,. Inflammasomes are caspase-1-containing protein complexes that promote inflammation,,. The NLRP3 inflammasome is among the most widely studied inflammasome members; it comprises NLRP3, an apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1,,. After its activation, pro-caspase-1 becomes activated and cleaves pro-interleukin-1β (IL-1β) and pro-IL-18 to form IL-1β and IL-18,,,. Activated caspase-1 can also cleave the gasdermin-D (GSDMD) protein; the N-terminal mature form of GSDMD (N-gasdermin) is oligomerized and inserted into the cell membrane to form pores for the release of IL-1β, IL-18,, and other danger-associated molecular patterns (DAMPs), such as high-mobility group box 1 (HMGB1) protein and S100 calcium-binding protein A9 (S100A9),,,,. IL-1β or IL-18 may aid HSC mobilization because of the injection of the NLRP3 inflammasome activation mediators IL-1β- or IL-18-induced HSC mobilization in mice,,,. Other DAMPs (HMGB1 and S100A9) are recognized by mannan-binding lectin, which then activates the complement system through mannan-binding lectin–associated serine proteinase. The activated complement C5a then lyses the erythrocytes and releases sphingosine-1-phosphate (S1P) into the peripheral blood to attract the HSCs mobilized from BM,,,,,,, [Figure 2].
|Figure 2: Granulocyte colony-stimulating factor induces hematopoietic stem cell mobilization by activating inflammasome and complement systems. Granulocyte colony-stimulating factor triggers monocytes and granulocytes to release eATP, which binds P2X4 or P2X7 on the surface of hematopoietic stem cells or innate immune cells to activate the NLRP3 inflammasome. Interleukin-1β, interleukin-18, and danger-associated molecular patterns are released through the pores formed by GSDMD. Danger-associated molecular patterns activate complement C5, releasing S1P from mature erythrocytes. Interleukin-1β, interleukin-18, and S1P together promote hematopoietic stem cell mobilization.|
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| Pain-sensing nerve cells (nociceptors) control hematopoietic stem cell mobilization|| |
Nociceptors belonging to sensory neurons can sense pain. These neurons have been well investigated in barrier tissues, such as the skin and gut; however, their biological role in nonbarrier tissues, such as BM remains unknown. Recently, a study demonstrated that BM nociceptors can be stimulated by G-CSF to release the neurotransmitter molecule calcitonin-gene-related peptide (CGRP). The administration of CGRP combined with G-CSF greatly improved HSC mobilization. CGRP binds directly to HSCs through a receptor dimer comprising the calcitonin receptor-like receptor (CALCRL) and receptor activity modifying protein 1 (RAMP1) and then mobilizes HSCs by activating downstream Gαs–adenylyl cyclase–cAMP signaling, [Figure 3]. Notably, feeding mice with capsaicin can stimulate the nociceptors to release CGRP and mobilize HSCs, [Figure 3].
|Figure 3: Granulocyte colony-stimulating factor and capsaicin mobilize hematopoietic stem cells by activating nociceptors in bone marrow. Granulocyte colony-stimulating factor and capsaicin stimulate nociceptors to release calcitonin-gene-related peptide and activates the downstream Gas–adenylyl cyclase–cAMP signaling through receptor (RAMP1/CALCRL) to promote hematopoietic stem cell mobilization.|
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| Conclusions|| |
G-CSF–triggered HSC mobilization is a complex process involving many mechanisms and niche cells, such as neutrophils, macrophages, sympathetic neurons, mesenchymal stem cells, osteoblasts, sinusoidal endothelial cells, granulocytes, monocytes, nociceptors, and erythroblasts. Other mechanisms remain to be discovered. For individuals who are poor mobilizers of G-CSF, a comprehensive understanding of the mechanisms underlying HSC mobilization is crucial to minimize HSC transplantation failure due to insufficient HSC mobilization. Researchers must attempt to develop a fast, accurate, sensitive, and simple screening method for identifying poor mobilizers and establish a new regimen for HSC mobilization.
We acknowledge Wallace Academic Editing for editing this manuscript.
Financial support and sponsorship
This work was supported by research funding from the Ministry of Science and Technology, Taiwan (MOST 103-2321-B-320-001, MOST105-2633-B-320-001, MOST106-2633-B-320-001, and MOST108-2311-B-320-001), Buddhist Tzu Chi Medical Foundation (TCMMP104-06 and TCMMP108-04), and Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan (TCRD106-42, TCRD108-55, and TCRD110-61).
Conflicts of interest
Prof. Hsin-Hou Chang, an editorial board member at Tzu Chi Med J, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.
| References|| |
Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 1978;4:7-25.
Man Y, Yao X, Yang T, Wang Y. Hematopoietic stem cell niche during homeostasis, malignancy, and bone marrow transplantation. Front Cell Dev Biol 2021;9:621214.
Tay J, Levesque JP, Winkler IG. Cellular players of hematopoietic stem cell mobilization in the bone marrow niche. Int J Hematol 2017;105:129-40.
Kumar SK, Callander NS, Hillengass J, Liedtke M, Baljevic M, Campagnaro E, et al. NCCN guidelines insights: Multiple myeloma, version 1.2020. J Natl Compr Canc Netw 2019;17:1154-65.
Copelan EA, Chojecki A, Lazarus HM, Avalos BR. Allogeneic hematopoietic cell transplantation; the current renaissance. Blood Rev 2019;34:34-44.
Horwitz SM, Ansell SM, Ai WZ, Barnes J, Barta SK, Choi M, et al. NCCN guidelines insights: T-cell lymphomas, version 2.2018. J Natl Compr Canc Netw 2018;16:123-35.
Horwitz SM, Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, et al. NCCN guidelines insights: Non-Hodgkin's lymphomas, version 3.2016. J Natl Compr Canc Netw 2016;14:1067-79.
Mehta PA, Faulkner LB. Hematopoietic cell transplantation for thalassemia: A global perspective BMT tandem meeting 2013. Biol Blood Marrow Transplant 2013;19:S70-3.
Dalle JH. Hematopoietic stem cell transplantation in SCD. C R Biol 2013;336:148-51.
Cheuk DK. Optimal stem cell source for allogeneic stem cell transplantation for hematological malignancies. World J Transplant 2013;3:99-112.
Chen J, Lazarus HM, Dahi PB, Avecilla S, Giralt SA. Getting blood out of a stone: Identification and management of patients with poor hematopoietic cell mobilization. Blood Rev 2021;47:100771.
Mueller MM, Bialleck H, Bomke B, Brauninger S, Varga C, Seidl C, et al. Safety and efficacy of healthy volunteer stem cell mobilization with filgrastim G-CSF and mobilized stem cell apheresis: Results of a prospective longitudinal 5-year follow-up study. Vox Sang 2013;104:46-54.
Hölig K, Kramer M, Kroschinsky F, Bornhäuser M, Mengling T, Schmidt AH, et al. Safety and efficacy of hematopoietic stem cell collection from mobilized peripheral blood in unrelated volunteers: 12 years of single-center experience in 3928 donors. Blood 2009;114:3757-63.
Pelus LM, Broxmeyer HE. Peripheral blood stem cell mobilization; a look ahead. Curr Stem Cell Rep 2018;4:273-81.
Giralt S, Costa L, Schriber J, Dipersio J, Maziarz R, McCarty J, et al. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: Consensus guidelines and recommendations. Biol Blood Marrow Transplant 2014;20:295-308.
Suarez-Alvarez B, Lopez-Vazquez A, Lopez-Larrea C. Mobilization and homing of hematopoietic stem cells. Adv Exp Med Biol 2012;741:152-70.
Levesque JP, Winkler IG. Mobilization of hematopoietic stem cells: State of the art. Curr Opin Organ Transplant 2008;13:53-8.
Takeyama K, Ohto H. PBSC mobilization. Transfus Apher Sci 2004;31:233-43.
Pusic I, Jiang SY, Landua S, Uy GL, Rettig MP, Cashen AF, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant 2008;14:1045-56.
Ataca Atilla P, Bakanay Ozturk SM, Demirer T. How to manage poor mobilizers for high dose chemotherapy and autologous stem cell transplantation? Transfus Apher Sci 2017;56:190-8.
Lévesque JP, Winkler IG, Larsen SR, Rasko JE. Mobilization of bone marrow-derived progenitors. Handb Exp Pharmacol 2007;80:3-36.
Lévesque JP, Hendy J, Winkler IG, Takamatsu Y, Simmons PJ. Granulocyte colony-stimulating factor induces the release in the bone marrow of proteases that cleave c-KIT receptor (CD117) from the surface of hematopoietic progenitor cells. Exp Hematol 2003;31:109-17.
Lévesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest 2003;111:187-96.
Lévesque JP, Hendy J, Takamatsu Y, Williams B, Winkler IG, Simmons PJ. Mobilization by either cyclophosphamide or granulocyte colony-stimulating factor transforms the bone marrow into a highly proteolytic environment. Exp Hematol 2002;30:440-9.
Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, et al.
Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002;109:625-37.
Lévesque JP, Takamatsu Y, Nilsson SK, Haylock DN, Simmons PJ. Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood 2001;98:1289-97.
Flomenberg N, Devine SM, Dipersio JF, Liesveld JL, McCarty JM, Rowley SD, et al. The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood 2005;106:1867-74.
Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 2005;201:1307-18.
Hess DA, Bonde J, Craft TP, Wirthlin L, Hohm S, Lahey R, et al.
Human progenitor cells rapidly mobilized by AMD3100 repopulate NOD/SCID mice with increased frequency in comparison to cells from the same donor mobilized by granulocyte colony stimulating factor. Biol Blood Marrow Transplant 2007;13:398-411.
Wang W, Yu S, Zimmerman G, Wang Y, Myers J, Yu VW, et al. Notch receptor-ligand engagement maintains hematopoietic stem cell quiescence and niche retention. Stem Cells 2015;33:2280-93.
Wang W, Yu S, Myers J, Wang Y, Xin WW, Albakri M, et al. Notch2 blockade enhances hematopoietic stem cell mobilization and homing. Haematologica 2017;102:1785-95.
Albakri M, Tashkandi H, Zhou L. A review of advances in hematopoietic stem cell mobilization and the potential role of Notch2 blockade. Cell Transplant 2020;29:963689720947146.
Rankin SM. Chemokines and adult bone marrow stem cells. Immunol Lett 2012;145:47-54.
Méndez-Ferrer S, Battista M, Frenette PS. Cooperation of beta (2)- and beta (3)-adrenergic receptors in hematopoietic progenitor cell mobilization. Ann N Y Acad Sci 2010;1192:139-44.
Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA, et al.
Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 2006;124:407-21.
Christopher MJ, Rao M, Liu F, Woloszynek JR, Link DC. Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice. J Exp Med 2011;208:251-60.
Chow A, Lucas D, Hidalgo A, Méndez-Ferrer S, Hashimoto D, Scheiermann C, et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med 2011;208:261-71.
Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F, et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 2010;116:4815-28.
Itkin T, Gur-Cohen S, Spencer JA, Schajnovitz A, Ramasamy SK, Kusumbe AP, et al. Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature 2016;532:323-8.
Broermann A, Winderlich M, Block H, Frye M, Rossaint J, Zarbock A, et al. Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo
. J Exp Med 2011;208:2393-401.
Nottebaum AF, Cagna G, Winderlich M, Gamp AC, Linnepe R, Polaschegg C, et al. VE-PTP maintains the endothelial barrier via plakoglobin and becomes dissociated from VE-cadherin by leukocytes and by VEGF. J Exp Med 2008;205:2929-45.
Singh P, Hoggatt J, Kamocka MM, Mohammad KS, Saunders MR, Li H, et al. Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells. J Clin Invest 2017;127:4527-40.
Itkin T, Gómez-Salinero JM, Rafii S. Open the gates: Vascular neurocrine signaling mobilizes hematopoietic stem and progenitor cells. J Clin Invest 2017;127:4231-4.
Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 2008;118:3820-8.
Ho BB, Bergwitz C. FGF23 signalling and physiology. J Mol Endocrinol 2021;66:R23-32.
Coe LM, Madathil SV, Casu C, Lanske B, Rivella S, Sitara D. FGF-23 is a negative regulator of prenatal and postnatal erythropoiesis. J Biol Chem 2014;289:9795-810.
Ishii S, Suzuki T, Wakahashi K, Asada N, Kawano Y, Kawano H, et al. FGF-23 from erythroblasts promotes hematopoietic progenitor mobilization. Blood 2021;137:1457-67.
Calvi LM. FGF-23: A novel actor in stem cell mobilization. Blood 2021;137:1434-6.
Cymer M, Brzezniakiewicz-Janus K, Bujko K, Thapa A, Ratajczak J, Anusz K, 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. Purinergic Signal 2020;16:313-25.
Lenkiewicz AM, Adamiak M, Thapa A, Bujko K, Pedziwiatr D, Abdel-Latif AK, et al. The Nlrp3 inflammasome orchestrates mobilization of bone marrow-residing stem cells into peripheral blood. Stem Cell Rev Rep 2019;15:391-403.
Liu D, Zeng X, Li X, Cui C, Hou R, Guo Z, et al. Advances in the molecular mechanisms of NLRP3 inflammasome activators and inactivators. Biochem Pharmacol 2020;175:113863.
Franchi L, Eigenbrod T, Núñez G. Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol 2009;183:792-6.
Cruz CM, Rinna A, Forman HJ, Ventura AL, Persechini PM, Ojcius DM. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J Biol Chem 2007;282:2871-9.
Adamiak M, Bujko K, Cymer M, Plonka M, Glaser T, Kucia M, et al. Novel evidence that extracellular nucleotides and purinergic signaling induce innate immunity-mediated mobilization of hematopoietic stem/progenitor cells. Leukemia 2018;32:1920-31.
Mangan MS, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov 2018;17:588-606.
Wen H, Miao EA, Ting JP. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 2013;39:432-41.
Franchi L, Eigenbrod T, Muñoz-Planillo R, Nuñez G. The inflammasome: A caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 2009;10:241-7.
Ito M, Shichita T, Okada M, Komine R, Noguchi Y, Yoshimura A, et al. Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat Commun 2015;6:7360.
Inoue M, Shinohara ML. NLRP3 inflammasome and MS/EAE. Autoimmune Dis 2013;2013:859145.
Groslambert M, Py BF. Spotlight on the NLRP3 inflammasome pathway. J Inflamm Res 2018;11:359-74.
Malik A, Kanneganti TD. Function and regulation of IL-1α in inflammatory diseases and cancer. Immunol Rev 2018;281:124-37.
Di A, Xiong S, Ye Z, Malireddi RK, Kometani S, Zhong M, et al. The TWIK2 potassium efflux channel in macrophages mediates NLRP3 inflammasome-induced inflammation. Immunity 2018;49:56-65.e4.
He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci 2016;41:1012-21.
Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 2015;526:660-5.
Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol 2013;13:397-411.
Kim SY, Son M, Lee SE, Park IH, Kwak MS, Han M, et al. High-mobility group box1-induced complement activation causes sterile inflammation. Front Immunol 2018;9:705.
Adamiak M, Abdel-Latif A, Ratajczak MZ. Purinergic signaling regulates mobilization of hematopoietic stem cells. Oncotarget 2018;9:36052-4.
Kang JW, Kim SJ, Cho HI, Lee SM. DAMPs activating innate immune responses in sepsis. Ageing Res Rev 2015;24:54-65.
Feldman N, Rotter-Maskowitz A, Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res Rev 2015;24:29-39.
Chen GY, Nuñez G. Sterile inflammation: Sensing and reacting to damage. Nat Rev Immunol 2010;10:826-37.
Ratajczak MZ, Bujko K, Cymer M, Thapa A, Adamiak M, Ratajczak J, et al. The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis. Leukemia 2020;34:1512-23.
Ratajczak MZ, Adamiak M, Thapa A, Bujko K, Brzezniakiewicz-Janus K, Lenkiewicz AM. NLRP3 inflammasome couples purinergic signaling with activation of the complement cascade for the optimal release of cells from bone marrow. Leukemia 2019;33:815-25.
Bujko K, Rzeszotek S, Hoehlig K, Yan J, Vater A, Ratajczak MZ. Signaling of the complement cleavage product anaphylatoxin C5a through C5aR (CD88) contributes to pharmacological hematopoietic stem cell mobilization. Stem Cell Rev Rep 2017;13:793-800.
Adamiak M, Ratajczak MZ. Innate immunity and mobilization of hematopoietic stem cells. Curr Stem Cell Rep 2017;3:172-80.
Ratajczak MZ, Lee H, Wysoczynski M, Wan W, Marlicz W, Laughlin MJ, et al. Novel insight into stem cell mobilization-plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex. Leukemia 2010;24:976-85.
Adamiak M, Abdelbaset-Ismail A, Suszynska M, Abdel-Latif A, Ratajczak J, Ratajczak MZ. Novel evidence that the mannan-binding lectin pathway of complement activation plays a pivotal role in triggering mobilization of hematopoietic stem/progenitor cells by activation of both the complement and coagulation cascades. Leukemia 2017;31:262-5.
Borkowska S, Suszynska M, Ratajczak J, Ratajczak MZ. Evidence of a pivotal role for the distal part of the complement cascade in the diurnal release of hematopoietic stem cells into peripheral blood. Cell Transplant 2016;25:275-82.
Dubin AE, Patapoutian A. Nociceptors: The sensors of the pain pathway. J Clin Invest 2010;120:3760-72.
Tikhonova AN, Aifantis I. Pain-sensing neurons mobilize blood stem cells from bone marrow. Nature 2021;589:520-1.
Gao X, Zhang D, Xu C, Li H, Caron KM, Frenette PS. Nociceptive nerves regulate haematopoietic stem cell mobilization. Nature 2021;589:591-6.
[Figure 1], [Figure 2], [Figure 3]