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Hematopoietic Stem Cell Mobilization Is Necessary but Not Sufficient for Tolerance in Islet Transplantation.
Stocks BT, Thomas AB, Elizer SK, Zhu Y, Marshall AF, Wilson CS, Moore DJ
(2017) Diabetes 66: 127-133
MeSH Terms: Allografts, Animals, Female, Flow Cytometry, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cell Transplantation, Islets of Langerhans Transplantation, Leukocyte Common Antigens, Mice, Mice, Inbred NOD, Osteoblasts
Show Abstract · Added November 1, 2016
Overcoming the immune response to establish durable immune tolerance in type 1 diabetes remains a substantial challenge. The ongoing effector immune response involves numerous immune cell types but is ultimately orchestrated and sustained by the hematopoietic stem cell (HSC) niche. We therefore hypothesized that tolerance induction also requires these pluripotent precursors. In this study, we determined that the tolerance-inducing agent anti-CD45RB induces HSC mobilization in nonautoimmune B6 mice but not in diabetes-prone NOD mice. Ablation of HSCs impaired tolerance to allogeneic islet transplants in B6 recipients. Mobilization of HSCs resulted in part from decreasing osteoblast expression of HSC retention factors. Furthermore, HSC mobilization required a functioning sympathetic nervous system; sympathectomy prevented HSC mobilization and completely abrogated tolerance induction. NOD HSCs were held in their niche by excess expression of CXCR4, which, when blocked, led to HSC mobilization and prolonged islet allograft survival. Overall, these findings indicate that the HSC compartment plays an underrecognized role in the establishment and maintenance of immune tolerance, and this role is disrupted in diabetes-prone NOD mice. Understanding the stem cell response to immune therapies in ongoing human clinical studies may help identify and maximize the effect of immune interventions for type 1 diabetes.
© 2017 by the American Diabetes Association.
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11 MeSH Terms
Skeletal trauma generates systemic BMP2 activation that is temporally related to the mobilization of CD73+ cells.
Marsell R, Steen B, Bais MV, Mortlock DP, Einhorn TA, Gerstenfeld LC
(2014) J Orthop Res 32: 17-23
MeSH Terms: 5'-Nucleotidase, Animals, Bone Marrow Cells, Bone Morphogenetic Protein 2, Cells, Cultured, Chemokine CXCL12, Disease Models, Animal, Flow Cytometry, Hematopoietic Stem Cell Mobilization, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL, Mice, Transgenic, Osteogenesis, Receptors, CXCR4, Stromal Cells, Tibia
Show Abstract · Added May 27, 2014
The relationship between BMP2 expression and the recruitment of skeletogenic stem cells was assessed following bone marrow reaming. BMP2 expression was examined using transgenic mice in which β-galactosidase had been inserted into the coding region of BMP2. Stem cell mobilization was analyzed by FACS analysis using CD73, a marker associated with bone marrow stromal stem cells. BMP2 expression was induced in endosteal lining cells, cortical osteocytes and periosteal cells in both the reamed and in contralateral bones. BMP2 mRNA expression in the reamed bone showed an early peak within the first 24 h of reaming followed by a later peak at 7 days, while contralateral bones only showed the 7 days peak of expression. FACS analysis sorting on CD73 positive cells showed a 50% increase of these cells at 3 and 14 days in the marrow of the injured bone and a single peak at 14 days of the marrow cell population of the contralateral bone. A ∼20% increase of CD73 positive cells was seen in the peripheral blood 2 days after reaming. These data showed that traumatic bone injury caused a systemic induction of BMP2 expression and that this increase is correlated with the mobilization of CD73 positive cells.
© 2013 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society.
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17 MeSH Terms
Differential stem- and progenitor-cell trafficking by prostaglandin E2.
Hoggatt J, Mohammad KS, Singh P, Hoggatt AF, Chitteti BR, Speth JM, Hu P, Poteat BA, Stilger KN, Ferraro F, Silberstein L, Wong FK, Farag SS, Czader M, Milne GL, Breyer RM, Serezani CH, Scadden DT, Guise TA, Srour EF, Pelus LM
(2013) Nature 495: 365-9
MeSH Terms: Animals, Anti-Inflammatory Agents, Non-Steroidal, Cell Count, Cell Movement, Cells, Cultured, Dinoprostone, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cells, Heterocyclic Compounds, Humans, Meloxicam, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteopontin, Papio, Receptors, Prostaglandin E, EP4 Subtype, Stem Cells, Thiazines, Thiazoles
Show Abstract · Added December 21, 2013
To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside in several, perhaps overlapping, niches that produce regulatory molecules and signals necessary for homeostasis and for increased output after stress or injury. Despite considerable advances in the specific cellular or molecular mechanisms governing HSC-niche interactions, little is known about the regulatory function in the intact mammalian haematopoietic niche. Recently, we and others described a positive regulatory role for prostaglandin E2 (PGE2) on HSC function ex vivo. Here we show that inhibition of endogenous PGE2 by non-steroidal anti-inflammatory drug (NSAID) treatment in mice results in modest HSC egress from the bone marrow. Surprisingly, this was independent of the SDF-1-CXCR4 axis implicated in stem-cell migration. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin. Haematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in other species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced E-prostanoid 4 (EP4) receptor signalling. These results not only uncover unique regulatory roles for EP4 signalling in HSC retention in the niche, but also define a rapidly translatable strategy to enhance transplantation therapeutically.
2 Communities
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20 MeSH Terms
Time is like a clock in my heart: implications for stem cell delivery after myocardial infarction.
Schoenhard JA, Hatzopoulos AK
(2010) Cardiology 117: 158-60
MeSH Terms: Hematopoietic Stem Cell Mobilization, Humans, Myocardial Infarction, Time Factors
Added November 18, 2010
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4 MeSH Terms
Comparison of outcomes after transplantation of G-CSF-stimulated bone marrow grafts versus bone marrow or peripheral blood grafts from HLA-matched sibling donors for patients with severe aplastic anemia.
Chu R, Brazauskas R, Kan F, Bashey A, Bredeson C, Camitta B, Chiang KY, Frangoul H, Gale RP, Gee A, George B, Goldman FD, Gross TG, Gupta V, Hale GA, Isola L, Ispizua AU, Lazarus H, Marsh J, Russell J, Sabloff M, Waller EK, Eapen M
(2011) Biol Blood Marrow Transplant 17: 1018-24
MeSH Terms: Adolescent, Adult, Anemia, Aplastic, Bone Marrow, Bone Marrow Transplantation, Cause of Death, Child, Female, Graft vs Host Disease, Granulocyte Colony-Stimulating Factor, HLA Antigens, Hematopoietic Stem Cell Mobilization, Histocompatibility, Humans, Leukocyte Count, Living Donors, Male, Middle Aged, Peripheral Blood Stem Cell Transplantation, Platelet Count, Postoperative Complications, Registries, Retrospective Studies, Siblings, Survival Rate, Transplantation Conditioning, Transplantation, Homologous, Treatment Outcome, Young Adult
Show Abstract · Added March 27, 2014
We compared outcomes of patients with severe aplastic anemia (SAA) who received granulocyte-colony stimulating factor (G-CSF)-stimulated bone marrow (G-BM) (n = 78), unstimulated bone marrow (BM) (n = 547), or peripheral blood progenitor cells (PBPC) (n = 134) from an HLA-matched sibling. Transplantations occurred in 1997 to 2003. Rates of neutrophil and platelet recovery were not different among the 3 treatment groups. Grade 2-4 acute graft-versus-host disease (aGVHD) (relative risk [RR] = 0.82, P = .539), grade 3-4 aGVHD (RR = 0.74, P = .535), and chronic GVHD (cGVHD) (RR = 1.56, P = .229) were similar after G-BM and BM transplants. Grade 2-4 aGVHD (RR = 2.37, P = .012) but not grade 3-4 aGVHD (RR = 1.66, P = .323) and cGVHD (RR = 5.09, P < .001) were higher after PBPC transplants compared to G-BM. Grade 2-4 (RR = 2.90, P < .001), grade 3-4 (RR = 2.24, P = .009) aGVHD and cGVHD (RR = 3.26, P < .001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR = 0.63, P = .05). These data suggest no advantage to using G-BM and the observed higher rates of aGVHD and cGVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA-matched sibling transplants for SAA.
2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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29 MeSH Terms
High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study.
Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, Gooley TA, Holmberg L, Henstorf G, LeMaistre CF, Mayes MD, McDonagh KT, McLaughlin B, Molitor JA, Nelson JL, Shulman H, Storb R, Viganego F, Wener MH, Seibold JR, Sullivan KM, Furst DE
(2007) Blood 110: 1388-96
MeSH Terms: Adult, Antigens, CD34, Antilymphocyte Serum, Combined Modality Therapy, Cyclophosphamide, Female, Fibrosis, Follow-Up Studies, Granulocyte Colony-Stimulating Factor, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cell Transplantation, Humans, Immunosuppressive Agents, Male, Middle Aged, Pilot Projects, Scleroderma, Systemic, Skin, Survival Rate, Transplantation, Autologous, Whole-Body Irradiation
Show Abstract · Added September 18, 2013
More effective therapeutic strategies are required for patients with poor-prognosis systemic sclerosis (SSc). A phase 2 single-arm study of high-dose immunosuppressive therapy (HDIT) and autologous CD34-selected hematopoietic cell transplantation (HCT) was conducted in 34 patients with diffuse cutaneous SSc. HDIT included total body irradiation (800 cGy) with lung shielding, cyclophosphamide (120 mg/kg), and equine antithymocyte globulin (90 mg/kg). Neutrophil and platelet counts were recovered by 9 (range, 7 to 13) and 11 (range, 7 to 25) days after HCT, respectively. Seventeen of 27 (63%) evaluable patients who survived at least 1 year after HDIT had sustained responses at a median follow-up of 4 (range, 1 to 8) years. There was a major improvement in skin (modified Rodnan skin score, -22.08; P < .001) and overall function (modified Health Assessment Questionnaire Disability Index, -1.03; P < .001) at final evaluation. Importantly, for the first time, biopsies confirmed a statistically significant decrease of dermal fibrosis compared with baseline (P < .001). Lung, heart, and kidney function, in general, remained clinically stable. There were 12 deaths during the study (transplantation-related, 8; SSc-related, 4). The estimated progression-free survival was 64% at 5 years. Sustained responses including a decrease in dermal fibrosis were observed exceeding those previously reported with other therapies. HDIT and autologous HCT for SSc should be evaluated in a randomized clinical trial.
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Mobilization of Ph chromosome-negative peripheral blood stem cells in a child with chronic myeloid leukemia after imatinib-induced complete molecular remission.
Woods-Swafford W, Vnencak-Jones CL, Loken MR, Manes B, Frangoul H
(2008) Pediatr Blood Cancer 50: 639-41
MeSH Terms: Antineoplastic Agents, Benzamides, Biomarkers, Tumor, Bone Marrow Purging, Child, Filgrastim, Forecasting, Fusion Proteins, bcr-abl, Granulocyte Colony-Stimulating Factor, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cells, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Myeloid, Chronic-Phase, Male, Peripheral Blood Stem Cell Transplantation, Piperazines, Protein Kinase Inhibitors, Pyrimidines, Recombinant Proteins, Remission Induction
Show Abstract · Added March 27, 2014
Chronic myelogenous leukemia (CML) is rare in the pediatric population. Allogeneic stem cell transplant remains the only curative therapy; however, identifying a fully matched donor is not always possible. Imatinib mesylate has been shown to induce hematologic and cytogenetic response in adults and children with CML. We describe a child who achieved molecular remission with imatinib mesylate. BCR-ABL negative peripheral blood stem cells (PBSC) were successfully collected after mobilization with filgrastim.
(c) 2007 Wiley-Liss, Inc.
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22 MeSH Terms
High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes.
McSweeney PA, Nash RA, Sullivan KM, Storek J, Crofford LJ, Dansey R, Mayes MD, McDonagh KT, Nelson JL, Gooley TA, Holmberg LA, Chen CS, Wener MH, Ryan K, Sunderhaus J, Russell K, Rambharose J, Storb R, Furst DE
(2002) Blood 100: 1602-10
MeSH Terms: Adult, Antigens, CD34, Antilymphocyte Serum, Combined Modality Therapy, Cyclophosphamide, Female, Granulocyte Colony-Stimulating Factor, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cell Transplantation, Humans, Immunosuppressive Agents, Male, Middle Aged, Pilot Projects, Scleroderma, Systemic, Survival Analysis, Transplantation, Autologous
Show Abstract · Added September 18, 2013
Systemic sclerosis (SSc) is a multisystem disease of presumed autoimmune pathogenesis for which no proven effective treatment exists. High-dose immunosuppressive therapy (HDIT) has been proposed as an investigational treatment for severe autoimmune diseases. Nineteen patients with poor-prognosis SSc underwent HDIT. The median age was 40 years (range, 23-61 years), the median modified Rodnan skin score (a measure of dermal sclerosis) was 31, and the median DLCO was 57%. Conditioning therapy involved 800 cGy total body irradiation (TBI) (+/- lung shielding to approximately 200 cGy), 120 mg/kg cyclophosphamide, and 90 mg/kg equine antithymocyte globulin. CD34-selected granulocyte-colony-stimulating factor-mobilized autologous blood stem cells provided hematopoietic rescue. With median follow-up at 14.7 months, the Kaplan-Meier estimated 2-year survival rate was 79%. Three patients died of treatment complications and one of disease progression. Two of the first 8 patients had fatal regimen-related pulmonary injury, a complication not found among 11 subsequent patients who received lung shielding for TBI. Overall, internal organ functions were stable to slightly worse after HDIT, and 4 patients had progressive or nonresponsive disease. As measured by modified Rodnan skin scores and modified health assessment questionnaire disability index (mHAQ-DI) scores, significant disease responses occurred in 12 of 12 patients evaluated at 1 year after HDIT. In conclusion, though important treatment-related toxicities occurred after HDIT for SSc, modifications of initial approaches appear to reduce treatment risks. Responses in skin and mHAQ-DI scores exceed those reported with other therapies, suggesting that HDIT is a promising new therapy for SSc that should be evaluated in prospective randomized studies.
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17 MeSH Terms
Pilot trial of interleukin-2 with granulocyte colony-stimulating factor for the mobilization of progenitor cells in advanced breast cancer patients undergoing high-dose chemotherapy: expansion of immune effectors within the stem-cell graft and post-stem-cell infusion.
Sosman JA, Stiff P, Moss SM, Sorokin P, Martone B, Bayer R, van Besien K, Devine S, Stock W, Peace D, Chen Y, Long C, Gustin D, Viana M, Hoffman R
(2001) J Clin Oncol 19: 634-44
MeSH Terms: Adult, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Carboplatin, Cyclophosphamide, Cytotoxicity, Immunologic, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Graft Survival, Granulocyte Colony-Stimulating Factor, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Infusions, Intraosseous, Interleukin-2, Middle Aged, Pilot Projects, Thiotepa
Show Abstract · Added March 5, 2014
PURPOSE - To evaluate whether administration of interleukin-2 (IL-2) with granulocyte colony-stimulating factor (G-CSF) improves mobilization of immune effector cells into the stem-cell graft of patients undergoing high-dose chemotherapy and autografting.
PATIENTS AND METHODS - We performed a trial of stem-cell mobilization with IL-2 and G-CSF in advanced breast cancer patients receiving high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin and stem cells followed by IL-2. The trial defined immune, hematologic, and clinical effects of IL-2 in this setting.
RESULTS - Of 32 patients enrolled, nine received G-CSF alone for mobilization. Twenty-one of 23 patients mobilized with IL-2 plus G-CSF had stem cells collected with more mononuclear cells than those receiving G-CSF (19.3 v 10.4 x 10(8)/kg; P =.006), but fewer CD34(+) progenitor cells (6.9 v 22.0 x 10(6)/kg; P =.049). The IL-2 plus G-CSF-mobilized patients had greater numbers of activated T (CD3(+)/CD25(+)) cells (P =.009), natural killer (NK; CD56(+)) cells (P =.007), and activated NK (CD56 bright(+)) cells (P: =.039) than those patients mobilized with G-CSF. NK (P =.042) and lymphokine-activated killer (LAK) (P =.016) activity was increased in those mobilized with IL-2 + G-CSF, whereas G-CSF-mobilized patients had a decline in cytolytic activity. In the third week posttransplantation, immune reconstitution was superior in those mobilized with IL-2 plus G-CSF based on greater numbers of activated T cells (P =.003), activated NK cells (P =.04), and greater LAK activity (P =.003). The 16 of 21 IL-2 + G-CSF-mobilized patients with adequate numbers of stem cells (> 1.5 x 10(6) CD34(+) cells/kg) collected engrafted rapidly posttransplantation.
CONCLUSION - The results demonstrate that G-CSF + IL-2 can enhance the number and function of antitumor effector cells in a mobilized autograft without impairing the hematologic engraftment, provided that CD34 cell counts are more than 1.5 x 10(6) cells/kg. Mobilization of CD34(+) stem cells does seem to be adversely affected. In those mobilized with IL-2 and G-CSF, post-stem-cell immune reconstitution of antitumor immune effector cells was enhanced.
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20 MeSH Terms