15-PGDH Inhibition Activates the Splenic Niche to Promote Hematopoietic Regeneration

AbstractThe splenic microenvironment regulates hematopoietic stem and progenitor cell (HSPC) function, particularly during demand-adapted hematopoiesis, however practical strategies to enhance splenic support of transplanted HSPCs have proven elusive. We have previously demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the small molecule (+)SW033291 (PGDHi), increases bone marrow (BM) prostaglandin E2 (PGE2) levels, expands HSPC numbers, and accelerates hematologic reconstitution following BM transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, specifically 15-PGDH high-expressing macrophages (MΦs), megakaryocytes (MKs), and mast cells (MCs), regulates steady-state hematopoiesis and potentiates recovery after BMT. Notably, PGDHi-induced neutrophil, platelet, and HSPC recovery were highly attenuated in splenectomized mice. PGDHi induced non-pathologic splenic extramedullary hematopoiesis at steady-state, and pre-transplant PGDHi enhanced the homing of transplanted cells to the spleen. 15-PGDH enzymatic activity localized specifically to MΦs, MK lineage cells, and MCs, identifying these cell types as likely coordinating the impact of PGDHi on splenic HSPCs. These findings suggest that 15-PGDH expression marks novel HSC niche cell types that regulate hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to therapeutically target multiple HSC niches and to promote hematopoietic regeneration and improve clinical outcomes of BMT.

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Neuronal regulation of bone marrow stem cell niches

F1000Research ◽

10.12688/f1000research.22554.1 ◽

2020 ◽

Vol 9 ◽

pp. 614 ◽

Cited By ~ 1

Author(s):

Claire Fielding ◽

Simón Méndez-Ferrer

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Steady State ◽

Sympathetic Innervation ◽

Hematopoietic Stem ◽

Regulatory Processes ◽

Lineage Differentiation ◽

Bm Niche ◽

Neuronal Regulation ◽

Hsc Niche

The bone marrow (BM) is the primary site of postnatal hematopoiesis and hematopoietic stem cell (HSC) maintenance. The BM HSC niche is an essential microenvironment which evolves and responds to the physiological demands of HSCs. It is responsible for orchestrating the fate of HSCs and tightly regulates the processes that occur in the BM, including self-renewal, quiescence, engraftment, and lineage differentiation. However, the BM HSC niche is disturbed following hematological stress such as hematological malignancies, ionizing radiation, and chemotherapy, causing the cellular composition to alter and remodeling to occur. Consequently, hematopoietic recovery has been the focus of many recent studies and elucidating these mechanisms has great biological and clinical relevance, namely to exploit these mechanisms as a therapeutic treatment for hematopoietic malignancies and improve regeneration following BM injury. The sympathetic nervous system innervates the BM niche and regulates the migration of HSCs in and out of the BM under steady state. However, recent studies have investigated how sympathetic innervation and signaling are dysregulated under stress and the subsequent effect they have on hematopoiesis. Here, we provide an overview of distinct BM niches and how they contribute to HSC regulatory processes with a particular focus on neuronal regulation of HSCs under steady state and stress hematopoiesis.

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Impairment of Hematopoietic Stem Cell (HSC) Niche by G-CSF Is Associated with Rapid Mobilization of Serially Reconstituting HSC and Reduced Competitive Repopulation of Mobilized Bone Marrow

Blood ◽

10.1182/blood.v118.21.1889.1889 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1889-1889 ◽

Cited By ~ 1

Author(s):

Jean-Pierre Levesque ◽

Valerie Barbier ◽

Bianca Nowlan ◽

Domenica McCarhty ◽

Ingrid G Winkler

Keyword(s):

Cell Cycle ◽

Bone Marrow ◽

Steady State ◽

Conflicts Of Interest ◽

Brdu Incorporation ◽

Down Regulation ◽

Hematopoietic Stem ◽

Post Transplant ◽

Donor Chimerism ◽

Hsc Niche

Abstract Abstract 1889 We have previously shown that G-CSF administration impairs HSC niches in the mobilized bone marrow (BM). G-CSF causes rapid suppression (within 2 days) of endosteal osteoblasts and bone formation with concomitant down-regulation of Kit ligand, CXCL12 and angiopoietin-1. This effect is mediated by the depletion of specific populations of BM macrophages1. Considering the very rapid impairment of HSC niches in response to G-CSF, we hypothesized that 1) the most primitive HSC should also mobilize at this very early stage within the first 48 hours of G-CSF treatment, and 2) that down-regulation of HSC niche function should also alter the number or function of HSC remaining in the mobilized BM. To test this, 125μg/kg rhuG-CSF was injected twice daily to C57BL/6 mice; blood and BM harvested at days 2 and 5 of G-CSF treatment to be transplanted into congenic recipients in a long-term competitive repopulation assay (LT-CR). Transplantation of 25μL blood showed a gradual increase in the number of LT-CR cells mobilized in response to G-CSF as measured by donor chimerism in myeloid and B lineages at 16 weeks post-transplant. Expectedly repopulating units (RU) per mL blood progressively increased from 0.2 ± 0.0 (n=6) in steady-state to 2.9 ± 1.6 (n=9) and 82.6 ± 40.4 (n=9) at days 2 and 5 of G-CSF treatment respectively. At 16 weeks post-transplant, BM from primary recipients were transplanted into secondary recipients. Surprisingly, secondary recipients of blood samples collected after 2 and 5 days of G-CSF treatment had equivalent levels of donor chimerism (37.2% ± 6.6% for 2 days G-CSF and 47.1% ± 7.8% for 5 days G-CSF, n = 8 per group). Therefore, although the absolute number of RU mobilized at day 2 of G-CSF was 28-fold lower than at day 5 of G-CSF administration, more primitive serially reconstituting HSC were mobilized at equivalent levels at days 2 and 5 of G-CSF treatment. This supports our hypothesis that most potent serially reconstituting HSC are mobilized as early as day 2 of G-CSF treatment consistent with the disappearance of osteoblasts1. To test the potential of HSC remaining in the BM, BM cells from G-CSF mobilized mice were transplanted in competition with BM cells from congenic mice in steady-state. Donor chimerism at 16 weeks post-transplant showed that competitive repopulation of BM cells was severely impaired at day 5 of G-CSF treatment with the number of RU per 200,000 BM cells decreasing from 4.1 ± 1.4 in steady-state and 5.2 ± 1.6 at day 2 of G-CSF treatment, to only 0.14 ± 0.05 at day 5 of G-CSF treatment. To test whether this 29-fold decrease in competitive repopulation was due to increased HSC proliferation, we measured BrdU incorporation for the last 2.5 days prior to BM harvest as well as cell cycle analysis with Ki67 and Hoechst33342. The proportion of quiescent Lin- Sca1+ Kit+ CD48- phenotypic HSC in G0 phase decreased from 62.8 ±4.0% in steady-state to 43.5±8.2% at day 2 of G-CSF, but surged back to 80.5±1.9% and 75.1±3.5% at days 3.5 and 5 of G-CSF treatment. The proportion of HSC in G1 and S/G2/M phases followed the opposite pattern, up at day 2, down at days 3.5 and 5. This was confirmed by BrdU incorporation for 2.5 days with the number of BrdU+ cells among Lin- Sca1+ KIT+ CD48- cells rising from 35.1±4.0% in steady-state, to 51.2±4.5% at day 2 of G-CSF and going down to 18.1±1.9% at day 3.5 and 23.3±5.5% at day 5 of G-CSF. Therefore, G-CSF recruits phenotypic HSC into cell cycle within the first 2 days of administration, but HSC return to quiescence despite continuing G-CSF. Therefore decreased repopulation potential at day5 of G-CSF is not due to increased cycling. Finally, we noted that the number of Lin-Sca1+KIT+CD48-CD150+ HSC and Lin-Sca1+KIT+CD48-CD150- multipotent progenitors were reduced 2.4- and 2.8-fold respectively (p<.05) in G-CSF-mobilized BM. In conclusion, administration of G-CSF rapidly disrupts HSC niches resulting in rapid mobilization of serially-reconstituting LT-CRC as early as day 2 of G-CSF administration. Secondly, the marked reduction of competitive reconstitution potential of mobilized BM was not due to increased HSC cycling but rather to decreased number of HSC remaining in mobilized BM. Disclosures: No relevant conflicts of interest to declare.

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27-Hydroxycholesterol Induces Hematopoietic Stem Cell Mobilization and Extramedullary Hematopoiesis Mediated By Estrogen Receptor Alpha

Blood ◽

10.1182/blood.v130.suppl_1.636.636 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 636-636

Author(s):

Hideyuki Oguro ◽

Jeffrey McDonald ◽

Sean Morrison

Keyword(s):

Bone Marrow ◽

Estrogen Receptor ◽

Steady State ◽

Sex Hormones ◽

Bone Marrow Cells ◽

Hematopoietic Cells ◽

Extramedullary Hematopoiesis ◽

Wild Type ◽

Hematopoietic Stem ◽

Deficient Mice

Abstract In adults, hematopoietic stem cells (HSCs) reside primarily in the bone marrow and their number is tightly regulated under steady state conditions. However, acute demands on the hematopoietic system promote HSC division and mobilization to extramedullary tissues such as the spleen, to increase production of blood cells. While the mechanisms that regulate HSC numbers and residence in the bone marrow under steady-state conditions have been extensively characterized, the mechanisms that activate HSCs in response to acute hematopoietic demands are less well understood. We have previously reported that extramedullary hematopoiesis (EMH) is induced during pregnancy when maternal blood volume expands rapidly. This requires HSC division and mobilization, processes that depend upon estrogen receptor α (ERα) in HSCs. Signaling through this nuclear hormone receptor can be triggered by sex hormones, such as 17β-estradiol (E2), as well as 27-hydroxycholesterol (27HC), which is the first identified endogenous ER ligand other than sex hormones. However, it has been unclear whether 27HC has a physiological role that is effected through ERα signaling in normal mice. Here we show that treatment of mice with E2, which increases during pregnancy, induced HSC division in the bone marrow but did not increase HSC number in the spleen, indicating that E2 treatment does not induce HSC mobilization. In contrast, treatment with the alternative endogenous ERα ligand, 27HC, increased HSC number in the spleen and induced EMH, but not HSC division in the bone marrow, indicating a role in inducing HSC mobilization. The effect of 27HC on HSC mobilization was nullified by deletion of Esr1 (the gene that encodes ERα) in hematopoietic cells using Vav1-icre ; Esr1fl/fl mice, indicating that 27HC-induced HSC mobilization is dependent on ERα. To test whether 27HC acts directly on HSCs, we competitively transplanted Vav1-icre ; Esr1fl/fl donor bone marrow cells along with wild-type competitor bone marrow cells and treated the recipient mice with 27HC four months after the transplantation. 27HC treated mice had significantly lower frequencies of donor-derived (Esr1- deficient) HSCs in the spleen as compared to vehicle-treated mice. This indicates that Esr1- deficient HSCs were at a disadvantage compared to wild-type HSCs in the same mice for mobilization in response to 27HC. ERα thus acts cell-autonomously within HSCs to promote mobilization in response to 27HC. 27HC is generated directly from cholesterol by the sterol hydroxylase, Cyp27a1, and plasma 27HC levels correlate with total cholesterol levels. It has been reported that mice with defects in cholesterol efflux exhibit increased mobilization of hematopoietic stem and progenitor cells (HSPCs) associated with increased serum granulocyte colony-stimulating factor (G-CSF) levels. However, we observed that G-CSF deficiency using Csf3-/- mice did not affect the magnitude of the increase in mobilized HSCs in response to 27HC treatment. Together, 27HC and G-CSF co-treatment additively increased the numbers of colony-forming HSPCs in the blood. Therefore, 27HC and G-CSF likely act through distinct mechanisms. During pregnancy, 27HC levels increased in HSPCs as a result of Cyp27a1. Cyp27a1 -deficient mice had significantly reduced 27HC levels but, under steady-state conditions, Cyp27a1 deficiency did not affect the numbers of HSCs and hematopoietic cells in both bone marrow and spleen. However, during pregnancy, Cyp27a1 -deficient mice had significantly reduced HSC mobilization and EMH, while the increased rate of HSC division and hematopoiesis in the bone marrow was not affected. In contrast, Cyp27a1 deficiency did not affect HSC mobilization and EMH in response to blood loss or G-CSF treatment. Distinct hematopoietic stresses thus induce EMH through different mechanisms. Taken together, these results indicate that two different endogenous ERα ligands, E2 and 27HC, work together to promote EMH during pregnancy, revealing a collaboration of hormone and lipid signaling as well as a physiological function for 27HC in normal mice. Disclosures No relevant conflicts of interest to declare.

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Oral intake of lipopolysaccharide regulates toll-like receptor 4-dependent granulopoiesis

Experimental Biology and Medicine ◽

10.1177/1535370220931043 ◽

2020 ◽

Vol 245 (14) ◽

pp. 1254-1259

Author(s):

Melanie Märklin ◽

Stefanie Bugl ◽

Stefan Wirths ◽

Julia-Stefanie Frick ◽

Martin R Müller ◽

...

Keyword(s):

Steady State ◽

Cell Fate ◽

Progenitor Cell ◽

Oral Intake ◽

Innate Immune ◽

Toll Like Receptor ◽

Gastrointestinal Microbiome ◽

Hematopoietic Stem ◽

Cell Fate Decisions ◽

The Impact

While neutrophil production in emergency states has been extensively studied, regulation of neutrophil homeostasis in the steady-state remained incompletely understood. We have shown that innate immune receptor toll-like receptor (TLR)4 and downstream TIR-domain-containing adapter-inducing interferon-β (TRIF) are indispensable for the generation of a granulocyte-colony stimulating factor (G-CSF)-dependent regulatory feedback loop upon antibody-induced neutropenia. These findings demonstrated that steady-state granulopoiesis is a demand-driven process, which may rely on differential triggering of innate immune receptors by microbial cell wall constituents such as lipopolysaccharide. Herein, we present further evidence on underlying mechanisms: oral intake of highly endotoxic lipopolysaccharide, but not TLR-antagonistic lipopolysaccharide derived from Rhodobacter sphaeroides, induces hematopoietic stem and progenitor cell fate decisions toward the neutrophil lineage independent of G-CSF. TLR4 has been identified as the indispensable sensor for oral lipopolysaccharide-modulated steady-state granulopoiesis. These results have important implications: food lipopolysaccharide content or the composition of the gastrointestinal microbiome may be strongly underrated as determinants of peripheral blood neutrophil levels. Both neutrophilia and neutropenia are associated with drastically worse outcomes in epidemiological studies of the general population as well as in diseased states. Impact statement In our present study, we investigated the impact of LPS on neutrophil homeostasis and found that oral intake is sufficient to induce hematopoietic stem and progenitor cell fate decisions towards the neutrophil lineage independent of G-CSF. In addition, TLR4 has been identified as the indispensable sensor for oral LPS-modulated steady-state granulopoiesis. We provide evidence that the gastrointestinal microbiome is critical for neutrophil homeostasis, which has implications for patients being treated with chemotherapy or antimicrobial therapy, since both are significantly influencing the composition of the intestinal microbiome.

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Inflammageing of Hematopoietic Stem Cells Is Driven By IL-1

Blood ◽

10.1182/blood-2019-130361 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 819-819

Author(s):

Larisa V. Kovtonyuk ◽

Francisco Caiado ◽

Emma Marie Caroline Slack ◽

Hitoshi Takizawa ◽

Markus G. Manz

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Steady State ◽

Hematopoietic Stem Cells ◽

Conflicts Of Interest ◽

Cell Types ◽

Extrinsic Factors ◽

Hematopoietic Stem ◽

Germ Free ◽

Lineage Differentiation

Introduction: Lifelong blood production is sustained through a stepwise differentiation program by a limited number of self-renewing hematopoietic stem cells (HSCs) in the bone marrow (BM). Hematopoietic cell development is tightly controlled by both cell-intrinsic and -extrinsic factors and its dysregulation can lead to aplasia or neoplasia. During ageing, HSCs increase in number, reduce self-renewal capacity on a per cell basis, skew towards myeloid differentiation, and show less efficient bone marrow (BM)-homing ability. We here evaluated how and to what extend HSC-extrinsic factors determine HSC behaviour during aging. Methods, Results and Discussion: To screen for aging-associated extrinsic factors, we performed antibody based protein arrays and transcriptome analysis with total BM of young (6-8 week old) versus aged (2 year old) animals. This demonstrated that RANTES, MIP-2, IL-1α and IL-1β are significantly upregulated in aged BM at both the protein as well as the RNA level. ELISA of peripheral blood (PB) serum and BM lysates indicated that IL-1α and IL-1β are locally increased and produced in BM, but are not significantly increased in PB serum. Further, qPCR of various BM cell types of hematopoietic (myeloid, lymphoid and progenitor cells) and non-hematopoietic/stromal origin indicated that multiple cell types upregulate Il1α and Il1β, with highest increase being derived from myeloid hematopoietic cells. This raised the possibility that elevated IL-1 is a result of an inflammatory response to circulating pathogen-derived compounds, possibly of bacterial origin. Indeed, we previously demonstrated that steady-state levels of granulopoiesis in young steady-state mice depend on heat-resistant microbiota-derived compounds (M.Balmer et al., The Journal of Immunology 2014). To prospectively test the role of IL-1-induced signalling and the microbiome during aging, we investigated the ageing-associated phenotype of HSCs in young and aged IL1RIKO mice and in young and aged germ-free mice. Both IL1RIKO and germ-free aged mice had lower counts of platelets and neutrophils in PB, and lower frequency of LT-HSCs (LKS Flt3-CD34-CD48-CD150+) in BM, compared to aged WT mice. Moreover, aged IL1RIKO LT-HSCs showed improved lymphoid lineage repopulation upon transplantation into lethally irradiated WT mice, compared to LT-HSCs of aged WT mice that demonstrated the known myeloid-biased lineage output. Interestingly, LT-HSCs from aged germ-free mice also demonstrated lymphoid-biased lineage differentiation as observed from young mice. In line with this finding, no difference was observed in IL-1α and IL-1β protein concentrations in BM lysates from young and aged germ-free mice. To test if IL-1 increase in aged steady-state mouse BM is indeed dependent on ligation of pattern recognition receptors and consecutive signalling, we analysed MyD88 and Trif KO mice, respectively. Both aged KO mice showed compared to WT mice reduced BM IL-1 levels and a reduced ageing-phenotype of HSCs, with the most profound difference in Trif KO mice. Interestingly, this correlates with our previous finding on pathogen-Induced TLR4-TRIF innate immune signaling in HSCs, inducing reduced competitive fitness (Takizawa et al., Cell Stem Cell 2017). Conclusions: Our data demonstrate that ageing associated phenotype and myeloid-biased differentiation of HSCs is a result of signals derived from the microbiome, that act through increased IL-1 signalling, locally in BM. Disclosures No relevant conflicts of interest to declare.

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Bone marrow stromal cells from MDS and AML patients show increased adipogenic potential with reduced Delta-like-1 expression

Scientific Reports ◽

10.1038/s41598-021-85122-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marie-Theresa Weickert ◽

Judith S. Hecker ◽

Michèle C. Buck ◽

Christina Schreck ◽

Jennifer Rivière ◽

...

Keyword(s):

Bone Marrow ◽

Cell Fate ◽

Stromal Cells ◽

Adipogenic Differentiation ◽

Cell Types ◽

Bone Marrow Niche ◽

Differentiation Potential ◽

Hematopoietic Stem ◽

Bm Niche

AbstractMyelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell disorders with a poor prognosis, especially for elderly patients. Increasing evidence suggests that alterations in the non-hematopoietic microenvironment (bone marrow niche) can contribute to or initiate malignant transformation and promote disease progression. One of the key components of the bone marrow (BM) niche are BM stromal cells (BMSC) that give rise to osteoblasts and adipocytes. It has been shown that the balance between these two cell types plays an important role in the regulation of hematopoiesis. However, data on the number of BMSC and the regulation of their differentiation balance in the context of hematopoietic malignancies is scarce. We established a stringent flow cytometric protocol for the prospective isolation of a CD73+ CD105+ CD271+ BMSC subpopulation from uncultivated cryopreserved BM of MDS and AML patients as well as age-matched healthy donors. BMSC from MDS and AML patients showed a strongly reduced frequency of CFU-F (colony forming unit-fibroblast). Moreover, we found an altered phenotype and reduced replating efficiency upon passaging of BMSC from MDS and AML samples. Expression analysis of genes involved in adipo- and osteogenic differentiation as well as Wnt- and Notch-signalling pathways showed significantly reduced levels of DLK1, an early adipogenic cell fate inhibitor in MDS and AML BMSC. Matching this observation, functional analysis showed significantly increased in vitro adipogenic differentiation potential in BMSC from MDS and AML patients. Overall, our data show BMSC with a reduced CFU-F capacity, and an altered molecular and functional profile from MDS and AML patients in culture, indicating an increased adipogenic lineage potential that is likely to provide a disease-promoting microenvironment.

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The Impact of Age and Gender on Hematopoietic Stem Cells and Immune Contexture of the Bone Marrow Microenvironment

Cells Tissues Organs ◽

10.1159/000510774 ◽

2020 ◽

pp. 1-6

Author(s):

Rebar N. Mohammed

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Immune Cells ◽

Absolute Number ◽

Cell Number ◽

Hematopoietic Stem ◽

The Absolute ◽

And Gender ◽

The Impact

Hematopoietic stem cells (HSCs) are a rare population of cells that reside mainly in the bone marrow and are capable of generating and fulfilling the entire hematopoietic system upon differentiation. Thirty-six healthy donors, attending the HSCT center to donate their bone marrow, were categorized according to their age into child (0–12 years), adolescence (13–18 years), and adult (19–59 years) groups, and gender into male and female groups. Then, the absolute number of HSCs and mature immune cells in their harvested bone marrow was investigated. Here, we report that the absolute cell number can vary considerably based on the age of the healthy donor, and the number of both HSCs and immune cells declines with advancing age. The gender of the donor (male or female) did not have any impact on the number of the HSCs and immune cells in the bone marrow. In conclusion, since the number of HSCs plays a pivotal role in the clinical outcome of allogeneic HSC transplantations, identifying a younger donor regardless the gender is critical.

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Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow

Journal of Experimental Medicine ◽

10.1084/jem.20110994 ◽

2012 ◽

Vol 209 (3) ◽

pp. 537-549 ◽

Cited By ~ 127

Author(s):

Anna Mansour ◽

Grazia Abou-Ezzi ◽

Ewa Sitnicka ◽

Sten Eirik W. Jacobsen ◽

Abdelilah Wakkach ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Hematopoietic Stem Cell ◽

Endochondral Ossification ◽

Osteoblastic Differentiation ◽

Hematopoietic Stem ◽

Mesenchymal Progenitors ◽

Hsc Niche ◽

Niche Formation

Formation of the hematopoietic stem cell (HSC) niche in bone marrow (BM) is tightly associated with endochondral ossification, but little is known about the mechanisms involved. We used the oc/oc mouse, a mouse model with impaired endochondral ossification caused by a loss of osteoclast (OCL) activity, to investigate the role of osteoblasts (OBLs) and OCLs in the HSC niche formation. The absence of OCL activity resulted in a defective HSC niche associated with an increased proportion of mesenchymal progenitors but reduced osteoblastic differentiation, leading to impaired HSC homing to the BM. Restoration of OCL activity reversed the defect in HSC niche formation. Our data demonstrate that OBLs are required for establishing HSC niches and that osteoblastic development is induced by OCLs. These findings broaden our knowledge of the HSC niche formation, which is critical for understanding normal and pathological hematopoiesis.

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Elevating body temperature enhances hematopoiesis and neutrophil recovery after total body irradiation in an IL-1–, IL-17–, and G-CSF–dependent manner

Blood ◽

10.1182/blood-2012-02-409805 ◽

2012 ◽

Vol 120 (13) ◽

pp. 2600-2609 ◽

Cited By ~ 19

Author(s):

Maegan L. Capitano ◽

Michael J. Nemeth ◽

Thomas A. Mace ◽

Christi Salisbury-Ruf ◽

Brahm H. Segal ◽

...

Keyword(s):

Heat Treatment ◽

Bone Marrow ◽

Body Temperature ◽

Total Body Irradiation ◽

Dependent Manner ◽

Intestinal Tissue ◽

Hematopoietic Stem ◽

Neutrophil Recovery ◽

Total Body ◽

The Impact

Abstract Neutropenia is a common side effect of cytotoxic chemotherapy and radiation, increasing the risk of infection in these patients. Here we examined the impact of body temperature on neutrophil recovery in the blood and bone marrow after total body irradiation (TBI). Mice were exposed to either 3 or 6 Gy TBI followed by a mild heat treatment that temporarily raised core body temperature to approximately 39.5°C. Neutrophil recovery was then compared with control mice that received either TBI alone heat treatment alone. Mice that received both TBI and heat treatment exhibited a significant increase in the rate of neutrophil recovery in the blood and an increase in the number of marrow hematopoietic stem cells and neutrophil progenitors compared with that seen in mice that received either TBI or heat alone. The combination treatment also increased G-CSF concentrations in the serum, bone marrow, and intestinal tissue and IL-17, IL-1β, and IL-1α concentrations in the intestinal tissue after TBI. Neutralizing G-CSF or inhibiting IL-17 or IL-1 signaling significantly blocked the thermally mediated increase in neutrophil numbers. These findings suggest that a physiologically relevant increase in body temperature can accelerate recovery from neutropenia after TBI through a G-CSF–, IL-17–, and IL-1–dependent mechanism.

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Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

BioMed Research International ◽

10.1155/2016/3071214 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Xin He ◽

YongBin Ye ◽

XiaoJun Xu ◽

Jing Wang ◽

YuXian Huang ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Cells ◽

Conditioning Regimen ◽

Clinical Manifestations ◽

Major Complication ◽

Clinical Situation ◽

Hematopoietic Stem ◽

T Cell Infiltration ◽

Bone Marrow Damage ◽

The Impact

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a major cause of nonrelapse mortality after allo-HSCT. A conditioning regimen plays a pivotal role in the development of aGVHD. To provide a platform for studying aGVHD and evaluating the impact of different conditioning regimens, we established a murine aGVHD model that simulates the clinical situation and can be conditioned with Busulfan-Cyclophosphamide (Bu-Cy) and Fludarabine-Busulfan (Flu-Bu). In our study, BALB/c mice were conditioned with Bu-Cy or Flu-Bu and transplanted with 2×107 bone marrow cells and 2×107 splenocytes from either allogeneic (C57BL/6) or syngeneic (BALB/c) donors. The allogeneic recipients conditioned with Bu-Cy had shorter survivals (P<0.05), more severe clinical manifestations, and higher hepatic and intestinal pathology scores, associated with increased INF-γ expression and diminished IL-4 expression in serum, compared to allogeneic recipients conditioned with Flu-Bu. Moreover, higher donor-derived T-cell infiltration and severely impaired B-cell development were seen in the bone marrow of mice, exhibiting aGVHD and conditioned with Flu-Bu. Our study showed that the conditioning regimen with Bu-Cy resulted in more severe aGVHD while the Flu-Bu regimen was associated with more extensive and long standing bone marrow damage.

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