Hematopoietic Progenitor Cells (HPC) from Mobilized Peripheral Blood Display Enhanced Migration and Marrow Homing Compared to Steady-State Bone Marrow HPC

Abstract

Objective-Faster engraftment of G-CSF mobilized peripheral blood (MPB) transplants compared to steady-state bone marrow (ssBM) is well documented and clinically relevant. A number of different factors likely contribute to this outcome. In the present study we explored whether independent of cell number there are intrinsic differences in the efficiency of progenitor cell homing to marrow between MPB and ssBM. Methods-Mobilization was achieved by continuous infusion of G-CSF alone or in combination with other mobilizing agents.In vivo homing assays, in vitro migration assays, gene expression analysis and flow cytometry were utilized to compare homing-related in vivo and in vitro properties of MPB and ssBM HPC.Results-Marrow homing of murine MPB HPC, generated by different mobilizing schemes, was reproducibly significantly superior to that of ssBM, in lethally irradiated as well as in non-irradiated hosts. This phenotype was independent of MMP9, selectins, β2-and α4-integrins. Superior homing was also observed for human MPB HPC transplanted into NOD/SCIDβ2microglobulin-/-recipients. Inhibition of HPC migration abrogated the homing advantage of MPB but did not affect homing of ssBM HPC, whereas enhancement of motility by CD26 inhibition improved marrow homing only of ssBM HPC. Enhanced SDF-1 dependent chemotaxis and low CD26 expression on MPB HPC were identified as potential contributing factors. Significant contributions of the putative alternative SDF-1 receptor, RDC1, were unlikely based on gene expression data. Conclusion-The data suggest increased motility as a converging end point of complex changes seen in MPB HPC which is likely responsible for their favorable homing.

Chemokine-mobilized adult stem cells; defining a better hematopoietic graft

“…This is in contrast with G-CSFmobilized cells that display enhanced migration to SDF-1 compared to marrow, low CD26 expression and marrow homing that is selectin and integrin independent. 58 The finding of a disconnect between in vitro migration to SDF1a and homing and engraftment of GROb-mobilized HSPC is contrary to the hypothesis that the SDF-1/CXCR4 axis is the primary axis involved in HSPC trafficking, engraftment and mobilization. 61,[85][86][87] Additional reports that WBC recovery is faster in patients transplanted with G-CSF-mobilized PBSC than bone marrow cells, 88,89 that G-CSF-mobilized CD34 þ cells migrate less well to SDF-1a in vitro than marrow CD34 þ cells, 70,90 that inhibition of Gai-coupled receptors, which includes CXCR4, by Pertusis toxin does not impair hematopoietic engraftment, 91 that fetal liver cells from CXCR4 À/À mice home and engraft in lethally irradiated recipients, 92 and that marrow engraftment of CXCR4 À/À and CXCR4 þ / þ SKL cells is equivalent 93 also suggest that the SDF-1a/CXCR4 axis may not be absolutely required for engraftment and homing by all HSC populations.…”

“…Recently, however, differential homing of G-CSF-mobilized stem cells resulting from enhanced motility and low CD26 expression relative to bone marrow stem cells have been suggested as contributing factors for enhanced engraftment. 58 Chemokine and chemokine receptor-induced stem cell mobilization…”

Innate immunity as orchestrator of stem cell mobilization

“…First, isolation of HSPCs from PB by leucopheresis is the easier and less stressful way to harvest such cells compared with multiple aspirations of BM cavities. Second, mobilized HSPCs engraft faster, 48 which results in accelerated recovery of blood platelets and granulocytes after transplantation. It is unfortunate that nearly 25% of patients, especially those pretreated with chemotherapy, do not respond efficiently to the currently recommended mobilization protocols and are deemed poor mobilizers.…”

Toward a More Effective Intravascular Cell Therapy in Stroke

“…Previous studies have explored different strategies to minimize lung adhesion and improve homing of systemically introduced cells: use of vasodilators (Schrepfer et al, 2007), pre-bolus injection of MSCs (Fischer et al, 2009), reducing the number of injected cells (Lee et al, 2009b), blockade of 6 and 4 integrins (Bonig et al, 2007;Qian et al, 2006;Bonig et al, 2009;Fischer et al, 2009), heparin saturation of MSCs (Deak et al, 2010) or preincubation of cells with white blood cells (Chute, 2006). Some beneficial effects on lung adhesion have been concluded, but the major mechanism behind this profound phenomenon is still unsolved.…”