DiPersio, John F

New England Journal of Medicine

English

Digital Commons@Becker

Washington University School of MedicineDigital Commons@BeckerOpen Access Publications2011Diabetic stem-cell "mobilopathy"John F. DiPersioWashington University School of Medicine in St. LouisFollow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubsThis Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in OpenAccess Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact engeszer@wustl.edu.Recommended CitationDiPersio, John F., ,"Diabetic stem-cell "mobilopathy"." The New England Journal of Medicine.365,26. 2536-2538. (2011).https://digitalcommons.wustl.edu/open_access_pubs/2910clinical implications of basic researchT h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 365;26 nejm.org december 29, 20112536Diabetic Stem-Cell “Mobilopathy”John F. DiPersio, M.D., Ph.D.Hematopoietic stem-cell (HSC) transplantation remains the primary curative treatment for pa-tients with a variety of hematologic cancers. Transplantation of either autologous or allogeneic stem cells requires the acquisition of sufficient numbers of HSCs to ensure rapid and consistent trilineage engraftment, thus minimizing extend-ed periods of pancytopenia after transplantation. Methods to optimize peripheralization of HSCs boost the number of HSCs that can be obtained for transplantation. These methods are based on the use of either cytokines alone (granulocyte colony-stimulating factor [G-CSF] or granulocyte–macrophage colony-stimulating factor [GM-CSF]) or cytokines plus chemotherapy to induce effec-tive egress of HSCs from the bone marrow into the peripheral blood, where they can be collected by means of apheresis. HSCs express CD34 and can thereby be captured and measured by means of flow cytometry.G-CSF and GM-CSF have been approved by the Food and Drug Administration for autologous and allogeneic stem-cell mobilization, but admin-istration of these cytokines with or without che-motherapy may still result in failure to mobilize sufficient numbers of cells for stem-cell trans-plantation.1 A disease state caused by failure to mobilize (“mobilopathy”) results not only in ad-ditional cost but also in increased morbidity and even the loss of transplantation as a curative op-tion for some patients. Recently, plerixafor (also called AMD3100), a small-molecule inhibitor of the CXC chemokine receptor 4 (CXCR4)–CXC chemokine ligand 12 (CXCL12) axis, was approved for stem-cell mobilization and has resulted in a modest reduction in failure rates when combined with G-CSF in patients with myeloma and lym-phoma.2 (CXCL12 is one of the ligands of CXCR4, and the CXCR4–CXCL12 axis is a critical tether that retains HSCs in the bone marrow and also guides their homing to the bone marrow.)There is considerable variation in the ability of the stem cells of patients and healthy donors to mobilize. The causes of mobilization failure remain unknown, but failure has been associated with older age, female sex, exposure to chemo-therapeutic agents that are toxic to the bone marrow, CD34 cells and platelets per cubic milli-meter of blood prior to mobilization, and genetic variants of CXCL12. Researchers’ understanding of the mechanisms involved in HSC mobilization and the dynamic forces that define the HSC niche has been dramatically expanded over the past decade.3,4 This niche can be dichotomized into vascular and endosteal compartments (Fig. 1). The endosteal or osteoblastic niche is defined by quiescent HSCs, osteoblasts expressing CXCL12 and the adhesion molecules vascular-cell adhe-sion molecule 1 and N-cadherin, supporting CD68+ macrophages (which release proteases), cytokines, and extracellular matrix proteins.Recent data suggest that G-CSF mediates the profound loss of CXCL12-positive osteoblasts and the down-regulation of CXCL12 expressed by nestin-expressing CXCL12-positive abundant re-ticular and mesenchymal cells. These nestin-posi-tive, CXCL12-positive abundant reticular cells, which in part define the vascular niche, are scat-tered throughout the marrow but primarily local-ize adjacent to the vascular sinusoids and are innervated directly and indirectly by β-adrenergic sympathetic nerves. G-CSF induces mobilization of HSCs from the endosteal and vascular niches through its direct effects on certain macro-phages and β-adrenergic sympathetic nerves, resulting in the loss of osteoblasts and dramatic down-regulation of CXCL12 in the osteoblasts that remain and in nestin-positive, CXCL12-posi-tive abundant reticular cells. G-CSF also triggers the release of putative and as yet unknown pro-teases that cleave the multiple tethers (such as CXCL12–CXCR4) that hold the HSCs in these niches. Most HSCs are located in close proximity to nestin-positive, CXCL12-positive abundant re-The New England Journal of Medicine Downloaded from nejm.org at WASHINGTON UNIV SCH MED MEDICAL LIB on May 27, 2014. For personal use only. No other uses without permission.  Copyright © 2011 Massachusetts Medical Society. All rights reserved. n engl j med 365;26 nejm.org december 29, 2011 2537clinical implications of basic researchWith Granulocyte Colony-Stimulating FactorNormal Bone Marrow Bone Marrow in Patients with DiabetesNestin-positiveCAR cellNestin-positiveCAR cellβ3-AdrenergicreceptorHematopoieticstem cellsIncreasedquiescent and cyclinghematopoieticstem cellsOsteoblastCXCL12expressionBWithout Granulocyte Colony-Stimulating FactorNormal Bone Marrow Bone Marrow in Patients with DiabetesACXCL12 expressionLowHighVascularsinusesEndothelialcellSympatheticneuronLoss ofosteoblastsCXCL12expressionCXCL12expressionCXCL12expressionTrabecularboneFigure 1. Hematopoietic Stem-Cell Mobilization in the Bone Marrow of Patients with Diabetes.The bone marrow niche consists of two major elements. The first element is the osteoblastic niche. Osteoblasts ex-press moderate levels of CXCL12 (pink) and bind hematopoietic stem cells (blue circles) that are primarily quiescent. The second element is the vascular niche, which is composed of vascular sinuses; lining endothelial cells; nestin-positive, CXCL12-positive abundant reticular (CAR) cells; β3-adrenergic receptors expressed on CAR cells; sympathetic neurons; and abundant hematopoietic stem cells. As shown in Panel A, the bone marrow microenvironment in patients with diabetes has increased numbers of quiescent hematopoietic stem cells (blue circles) and cycling hematopoietic stem cells (conjoined blue forms) and reduced numbers of osteoblasts and increased numbers of sympathetic neurons and β3-adrenergic receptors. As shown in Panel B, granulocyte colony-stimulating factor depletes osteoblasts and reduces CXCL12 expression in both osteoblasts and CAR cells, resulting in transmigration of hematopoietic stem cells into the vascular sinuses (peripheral circulation). Granulocyte colony-stimulating factor induces a similar reduc-tion of osteoblasts and CXCL12 expression in osteoblasts (white) but no reduction of CXCL12 expression (red) in the marrow of patients with diabetes as compared with normal marrow, resulting in a reduction in transmigration and mobilization of hematopoietic stem cells associated with CAR cells into the vascular sinuses (peripheral circulation).The New England Journal of Medicine Downloaded from nejm.org at WASHINGTON UNIV SCH MED MEDICAL LIB on May 27, 2014. For personal use only. No other uses without permission.  Copyright © 2011 Massachusetts Medical Society. All rights reserved. n engl j med 365;26 nejm.org december 29, 20112538clinical implications of basic researchticular cells that may, possibly through interac-tion with CXCL12, maintain the quiescence and stem-cell–like characteristics of HSCs.Ferraro et al.5 recently reported that diabetes is a disease that both interrupts the dynamic anatomy of the niche and induces HSC-indepen-dent and bone marrow microenvironment–depen-dent defects in G-CSF–induced HSC mobiliza-tion. They first showed, in a small and highly selected cohort of patients undergoing autolo-gous transplantation, that elevated blood glucose and glycated hemoglobin levels are more com-mon in patients in whom HSCs failed to mobi-lize into the peripheral-blood system. They next observed impaired G-CSF–induced HSC mobili-zation in mouse models of diabetes. Although the total number and percentages of long-term HSCs in the bone marrow of streptozocin-treat-ed mice (a mouse model of diabetes) were ele-vated as compared with those of untreated mice, there was no commensurate elevation in levels of circulating HSCs — suggesting a defect in the trafficking of HSCs out of the bone marrow at rest. The preference of HSCs for the bone mar-row in mice with diabetes was lost when they were transplanted into healthy mice, further demonstrating that the defect was not HSC- intrinsic but rather was due to the altered bone marrow microenvironment of mice with diabetes.Consistent with these findings was the ob-servation by Ferraro et al. that normal HSCs homed to the marrow more rapidly and prolifer-ated (in the marrow) more vigorously when in-jected into mice with diabetes as compared with the behaviors of these cells in healthy mice. Treatment of healthy mice with G-CSF resulted in the expected loss of osteoblasts and in CXCL12 expression in osteoblasts and nestin-positive, CXCL12-positive abundant reticular cells, com-mensurate with vigorous HSC mobilization. In contrast, treatment of diabetic mice with G-CSF resulted in an expected loss of osteoblasts and down-regulation of CXCL12 expressed by osteo-blasts, but no change in the expression of CXCL12 by nestin-positive, CXCL12-positive abun-dant reticular cells, resulting in a dramatic re-duction in G-CSF–mediated HSC mobilization (Fig. 1B).Defects in HSC mobilization after treatment of mice with β3-adrenergic receptor agonists as well as studies showing that genetic depletion of osteoblasts in mice with diabetes resulted in complete elimination of any residual mobilization induced by G-CSF all support the authors’ hy-pothesis that altered G-CSF–induced mobiliza-tion in mice with diabetes was due to a defect in the activation of the sympathetic nervous sys-tem (in spite of increased numbers of sympa-thetic nerve fibers in the bone marrow of mice with diabetes). This defect results in a function-al blockade of G-CSF–induced down-regulation of CXCL12 in nestin-positive, CXCL12-positive abundant reticular cells, the major CXCL12– expressing resident cells of the vascular niche. The authors suggest that this defect could be overcome with the use of plerixafor with or with-out G-CSF. Since plerixafor is a weaker mobiliz-ing agent than G-CSF, it is possible but unlikely that it can mediate the successful stem-cell mo-bilization in the patients with diabetes in whom stem cells fail to mobilize after the administra-tion of G-CSF alone. Only future prospective clinical trials can answer this question.One can only assume that many groups will now look closely at larger and less selected co-horts of both patients and healthy donors to see whether this preclinical observation holds up clinically. If it does, the use of alternative and optimal mobilization approaches (G-CSF plus plerixafor or G-CSF plus chemotherapy) could be used as early treatment in patients with dia-betes to limit the odds of mobilization failure and the number of patients requiring second mobilizations or allogeneic stem-cell transplan-tation for potentially curative therapy.Disclosure forms provided by the author are available with the full text of this article at NEJM.org.From the Division of Oncology, Washington University School of Medicine, St. Louis.1. Pusic I, Jiang SY, Landua S, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant 2008;14:1045-56.2. DiPersio JF, Micallef IN, Stiff PJ, et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with pla-cebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin’s lymphoma. J Clin Oncol 2009;27:4767-73.3. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 2006;25: 977-88.4. Méndez-Ferrer S, Michurina TV, Ferraro F, et al. Mesenchy-mal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010;466:829-34.5. Ferraro F, Lymperi S, Mendez-Ferrer S, et al. Diabetes im-pairs hematopoietic stem cell mobilization by altering niche function. Sci Transl Med 2011;3(104):104ra101.Copyright © 2011 Massachusetts Medical Society.The New England Journal of Medicine Downloaded from nejm.org at WASHINGTON UNIV SCH MED MEDICAL LIB on May 27, 2014. For personal use only. No other uses without permission.  Copyright © 2011 Massachusetts Medical Society. All rights reserved. 

Diabetic stem-cell  mobilopathy

John F. DiPersio

Crossref

Diabetic Stem-Cell “Mobilopathy”

https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=3913&amp;context=open_access_pubs

Diabetic stem-cell mobilopathy

Abstract

Similar works

Full text

Available Versions

Digital Commons@Becker

Crossref