New Insights in the Mobilization of Hematopoietic Stem Cells in Lymphoma and Multiple Myeloma Patients

Abstract

Following chemotherapy and/or the administration of growth factors, such as granulocyte-colony stimulated factor (G-CSF), hematopoietic stem cells (HSC) mobilize from bone marrow to peripheral blood. This review aims to systematically present the structure of the HSC “niche” and elucidate the mechanisms of their mobilization. However, this field is constantly evolving and new pathways and molecules have been shown to contribute to the mobilization process. Understanding the importance and the possible primary pathophysiologic role of each pathway is rather difficult, since they share various overlapping components. The primary initiating event for the mobilization of HSC is chemotherapy-induced endogenous G-CSF production or exogenous G-CSF administration. G-CSF induces proliferation and expansion of the myelomonocytic series, which leads to proteolytic enzyme activation. These enzymes result in disruption of various receptor-ligand bonds, which leads to the disanchorage of HSC from the bone marrow stroma. In everyday clinical practice, CXC chemokine receptor-4 (CXCR4) antagonists are now being used as mobilization agents in order to improve HSC collection. Furthermore, based on the proposed mechanisms of HSC mobilization, novel mobilizing agents have been developed and are currently evaluated in preclinical and clinical studies.

Relative frequency of immature CD34+/CD90+ subset in peripheral blood following mobilization correlates closely and inversely with the absolute count of harvested stem cells in multiple myeloma patients

“…In this study an intriguing observation is the inverse relationship between relative frequencies of the CD90 + SC ish and absolute counts of the total SC ish in PB, suggesting that continual increase in absolute counts of the total SC ish , during the G-CSF-induced mobilization, is not followed by an appropriate increase in the CD90 + cells. The G-CSF actingeither as an endogenously produced after chemotherapy or as exogenous or administered factor (rHuG-CSF), or a combination of both -is considered to be an initial signal for HSC mobilization, explained by several proposed pathways 24 . Nevertheless, there are data describing the superior effects of some new agents, such as mozobil or plerixafor (which is an antagonist of the alpha chemokine receptor CXCR4) in mobilizing the immature HSC, capable for long-term repopulation (LT-HSC) 25 .…”

New agents in HSC mobilization

“…In a separate study, fully human shark antibody-mimicking protein scaffolds termed "i-bodies" that target CXCR4 were found to inhibit HIV infection, cell migration and leukocyte recruitment but did not mobilize HSPC in either mice or humanized xenograft mouse models [50]. Similar to CXCR4 i-bodies, anti-CXCR4-and anti-SDF-1-blocking antibodies also fail to mobilize HSC [51] and support the notion that direct inhibition of CXCR4/SDF-1 chemotaxis by CXCR4 antagonists is only partially responsible for HSC mobilization and likely requires perturbation of CXCR4-dependent downstream signalling (Reviewed in [52]). Indeed, additional mechanisms for AMD3100-mediated HSC mobilization has been attributed to ROS signalling and CXCR4-dependent SDF-1 release [53] as well as AMD3100-induced reduction of BM vascular integrity and increased vascular permeability [54].…”

Granulocyte Colony-Stimulating Factor Induces Osteoblast Inhibition by B Lymphocytes and Osteoclast Activation by T Lymphocytes during Hematopoietic Stem/Progenitor Cell Mobilization

“…Compared with steady state, B lymphocytes produce more Dkk1 in the mobilized state, suggesting that B lymphocytes participate in G-CSFeinduced endosteal osteoblast inhibition. Recently, the CXCR4 antagonist was found to progressively replace G-CSF to mobilize HSPCs for autologous transplants in patients who failed prior mobilization with G-CSF [25][26][27]. Data showed that although AMD3100 was effective at mobilizing HSPCs, it did not suppress osteoblasts, endosteal cytokine expression, or reconstitution potential of HSPCs remaining in the mobilized BM [28].…”