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Ischemic stroke activates hematopoietic bone marrow stem cells.

ABSTRACT: The mechanisms leading to an expanded neutrophil and monocyte supply after stroke are incompletely understood.To test the hypothesis that transient middle cerebral artery occlusion (tMCAO) in mice leads to activation of hematopoietic bone marrow stem cells.Serial in vivo bioluminescence reporter gene imaging in mice with tMCAO revealed that bone marrow cell cycling peaked 4 days after stroke (P<0.05 versus pre tMCAO). Flow cytometry and cell cycle analysis showed activation of the entire hematopoietic tree, including myeloid progenitors. The cycling fraction of the most upstream hematopoietic stem cells increased from 3.34%±0.19% to 7.32%±0.52% after tMCAO (P<0.05). In vivo microscopy corroborated proliferation of adoptively transferred hematopoietic progenitors in the bone marrow of mice with stroke. The hematopoietic system's myeloid bias was reflected by increased expression of myeloid transcription factors, including PU.1 (P<0.05), and by a decline in lymphocyte precursors. In mice after tMCAO, tyrosine hydroxylase levels in sympathetic fibers and bone marrow noradrenaline levels rose (P<0.05, respectively), associated with a decrease of hematopoietic niche factors that promote stem cell quiescence. In mice with genetic deficiency of the ?3 adrenergic receptor, hematopoietic stem cells did not enter the cell cycle in increased numbers after tMCAO (naive control, 3.23±0.22; tMCAO, 3.74±0.33, P=0.51).Ischemic stroke activates hematopoietic stem cells via increased sympathetic tone, leading to a myeloid bias of hematopoiesis and higher bone marrow output of inflammatory Ly6C(high) monocytes and neutrophils.

SUBMITTER: Courties G

PROVIDER: S-EPMC4312511 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Ischemic stroke activates hematopoietic bone marrow stem cells.

Courties Gabriel G Herisson Fanny F Sager Hendrik B HB Heidt Timo T Ye Yuxiang Y Wei Ying Y Sun Yuan Y Severe Nicolas N Dutta Partha P Scharff Jennifer J Scadden David T DT Weissleder Ralph R Swirski Filip K FK Moskowitz Michael A MA Nahrendorf Matthias M

Circulation research 20141031 3

<h4>Rationale</h4>The mechanisms leading to an expanded neutrophil and monocyte supply after stroke are incompletely understood.<h4>Objective</h4>To test the hypothesis that transient middle cerebral artery occlusion (tMCAO) in mice leads to activation of hematopoietic bone marrow stem cells.<h4>Methods and results</h4>Serial in vivo bioluminescence reporter gene imaging in mice with tMCAO revealed that bone marrow cell cycling peaked 4 days after stroke (P<0.05 versus pre tMCAO). Flow cytometry ...[more]

PMID: 25362208

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Project description:The hematopoietic stem cell engraftment depends on adequate cell numbers, their homing, and the subsequent short and long-term engraftment of these cells in the niche. We performed a systematic review of the methods employed to track hematopoietic reconstitution using molecular imaging. We searched articles indexed, published prior to January 2020, in PubMed, Cochrane, and Scopus with the following keyword sequences: (Hematopoietic Stem Cell OR Hematopoietic Progenitor Cell) AND (Tracking OR Homing) AND (Transplantation). Of 2191 articles identified, only 21 articles were included in this review, after screening and eligibility assessment. The cell source was in the majority of bone marrow from mice (43%), followed by the umbilical cord from humans (33%). The labeling agent had the follow distribution between the selected studies: 14% nanoparticle, 29% radioisotope, 19% fluorophore, 19% luciferase, and 19% animal transgenic. The type of graft used in the studies was 57% allogeneic, 38% xenogeneic, and 5% autologous, being the HSC receptor: 57% mice, 9% rat, 19% fish, 5% for dog, porcine and salamander. The imaging technique used in the HSC tracking had the following distribution between studies: Positron emission tomography/single-photon emission computed tomography 29%, bioluminescence 33%, fluorescence 19%, magnetic resonance imaging 14%, and near-infrared fluorescence imaging 5%. The efficiency of the graft was evaluated in 61% of the selected studies, and before one month of implantation, the cell renewal was very low (less than 20%), but after three months, the efficiency was more than 50%, mainly in the allogeneic graft. In conclusion, our review showed an increase in using noninvasive imaging techniques in HSC tracking using the bone marrow transplant model. However, successful transplantation depends on the formation of engraftment, and the functionality of cells after the graft, aspects that are poorly explored and that have high relevance for clinical analysis.

Project description:BACKGROUND:Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative therapeutic approach for different hematological malignancies (HMs), and epigenetic modifications, including DNA methylation, play a role in the reconstitution of the hematopoietic system after AHSCT. This study aimed to explore global DNA methylation dynamic of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) from donors and their respective recipients affected by acute myeloid leukemia (AML), acute lymphoid leukemia (ALL) and Hodgkin lymphoma (HL) during the first year after transplant. METHODS:We measured DNA methylation profile by Illumina HumanMethylationEPIC in BM HSPC of 10 donors (t0) and their matched recipients at different time points after AHSCT, at day +?30 (t1), +?60 (t2), +?120 (t3), +?180 (t4), and +?365 (t5). Differential methylation analysis was performed by using R software and CRAN/Bioconductor packages. Gene set enrichment analysis was carried out on promoter area of significantly differentially methylated genes by clusterProfiler package and the mSigDB genes sets. RESULTS:Results show significant differences in the global methylation profile between HL and acute leukemias, and between patients with mixed and complete chimerism, with a strong methylation change, with prevailing hyper-methylation, occurring 30?days after AHSCT. Functional analysis of promoter methylation changes identified genes involved in hematopoietic cell activation, differentiation, shaping, and movement. This could be a consequence of donor cell "adaptation" in recipient BM niche. Interestingly, this epigenetic remodeling was reversible, since methylation returns similar to that of donor HSPCs after 1 year. Only for a pool of genes, mainly involved in dynamic shaping and trafficking, the DNA methylation changes acquired after 30?days were maintained for up to 1 year post-transplant. Finally, preliminary data suggest that the methylation profile could be used as predictor of relapse in ALL. CONCLUSIONS:Overall, these data provide insights into the DNA methylation changes of HSPCs after transplantation and a new framework to investigate epigenetics of AHSCT and its outcomes.

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Ischemic stroke activates hematopoietic bone marrow stem cells.

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Ischemic stroke activates hematopoietic bone marrow stem cells.

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