Publications by authors named "Moritz Middelhoff"

16 Publications

  • Page 1 of 1

Notch signaling drives development of Barrett's metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa.

Sci Rep 2021 Feb 24;11(1):4509. Epub 2021 Feb 24.

Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany.

Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.
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http://dx.doi.org/10.1038/s41598-021-84011-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904766PMC
February 2021

Extracorporeal multiorgan support including CO-removal with the ADVanced Organ Support (ADVOS) system for COVID-19: A case report.

Int J Artif Organs 2021 Apr 28;44(4):288-294. Epub 2020 Sep 28.

Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar der Technischen Universität München, München, Germany.

A substantial part of COVID-19-patients suffers from multi-organ failure (MOF). We report on an 80-year old patient with pulmonary, renal, circulatory, and hepatic failure. We decided against the use of extracorporeal membrane oxygenation (ECMO) due to old age and a SOFA-score of 13. However, the patient was continuously treated with the extracorporeal multi-organ- "ADVanced Organ Support" (ADVOS) device (ADVITOS GmbH, Munich, Germany). During eight 24h-treatment-sessions blood flow (100-300 mL/min), dialysate flow (160-320 mL/min) and dialysate pH (7.6-9.0) were adapted to optimize arterial PaCO and pH. Effective CO removal and correction of acidosis could be demonstrated by mean arterial- versus post-dialyzer values of pCO (68.7 ± 13.8 vs. 26.9 ± 11.6 mmHg;  < 0.001). The CO-elimination rate was 48 ± 23mL/min. The initial vasopressor requirement could be reduced in parallel to pH-normalization. Interruptions of ADVOS-treatment repeatedly resulted in reversible deteriorations of pCO and pH. After 95 h of continuous extracorporeal decarboxylating therapy the patient had markedly improved circulatory parameters compared to baseline. In the context of secondary pulmonary infection and progressive liver failure, the patient had a sudden cardiac arrest. In accordance with the presumed patient will, we decided against mechanical resuscitation. Irrespective of the outcome we conclude that extracorporeal CO removal and multiorgan-support were feasible in this COVID-19-patient. Combined and less invasive approaches such as ADVOS might be considered in old-age-COVID-19 patients with MOF.
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http://dx.doi.org/10.1177/0391398820961781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041450PMC
April 2021

Mist1+ gastric isthmus stem cells are regulated by Wnt5a and expand in response to injury and inflammation in mice.

Gut 2021 Apr 24;70(4):654-665. Epub 2020 Jul 24.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA

Background And Aims: The gastric epithelium undergoes continuous turnover. Corpus epithelial stem cells located in the gastric isthmus serve as a source of tissue self-renewal. We recently identified the transcription factor Mist1 as a marker for this corpus stem cell population that can give rise to cancer. The aim here was to investigate the regulation of the Mist1+ stem cells in the response to gastric injury and inflammation.

Methods: We used Mist1CreERT;R26-Tdtomato mice in two models of injury and inflammation: the acetic acid-induced ulcer and infection with . We analysed lineage tracing at both early (7 to 30 days) and late (30 to 90 days) time points. Mist1CreERT;R26-Tdtomato;Lgr5DTR-eGFP mice were used to ablate the corpus basal Lgr5+ cell population. Constitutional and conditional Wnt5a knockout mice were used to investigate the role of Wnt5a in wound repair and lineage tracing from the Mist1+ stem cells.

Results: In both models of gastric injury, Mist1+ isthmus stem cells more rapidly proliferate and trace entire gastric glands compared with the normal state. In regenerating tissue, the number of traced gastric chief cells was significantly reduced, and ablation of Lgr5+ chief cells did not affect Mist1-derived lineage tracing and tissue regeneration. Genetic deletion of Wnt5a impaired proliferation in the gastric isthmus and lineage tracing from Mist1+ stem cells. Similarly, depletion of innate lymphoid cells, the main source of Wnt5a, also resulted in reduced proliferation and Mist1+ isthmus cell tracing.

Conclusion: Gastric Mist1+ isthmus cells are the main supplier of regenerated glands and are activated in part through Wnt5a pathway.
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http://dx.doi.org/10.1136/gutjnl-2020-320742DOI Listing
April 2021

Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche.

Nat Commun 2020 01 8;11(1):111. Epub 2020 Jan 8.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA.

The enteric neurotransmitter acetylcholine governs important intestinal epithelial secretory and immune functions through its actions on epithelial muscarinic Gq-coupled receptors such as M3R. Its role in the regulation of intestinal stem cell function and differentiation, however, has not been clarified. Here, we find that nonselective muscarinic receptor antagonism in mice as well as epithelial-specific ablation of M3R induces a selective expansion of DCLK1-positive tuft cells, suggesting a model of feedback inhibition. Cholinergic blockade reduces Lgr5-positive intestinal stem cell tracing and cell number. In contrast, Prox1-positive endocrine cells appear as primary sensors of cholinergic blockade inducing the expansion of tuft cells, which adopt an enteroendocrine phenotype and contribute to increased mucosal levels of acetylcholine. This compensatory mechanism is lost with acute irradiation injury, resulting in a paucity of tuft cells and acetylcholine production. Thus, enteroendocrine tuft cells appear essential to maintain epithelial homeostasis following modifications of the cholinergic intestinal niche.
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http://dx.doi.org/10.1038/s41467-019-13850-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949263PMC
January 2020

BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice.

Gastroenterology 2019 03 15;156(4):1066-1081.e16. Epub 2018 Nov 15.

Division of Digestive and Liver Disease, Department of Medicine, Columbia University, New York, New York. Electronic address:

Background & Aims: The intestinal epithelium is maintained by long-lived intestinal stem cells (ISCs) that reside near the crypt base. Above the ISC zone, there are short-lived progenitors that normally give rise to lineage-specific differentiated cell types but can dedifferentiate into ISCs in certain circumstances. However, the role of epithelial dedifferentiation in cancer development has not been fully elucidated.

Methods: We performed studies with Bhlha15-CreERT, Lgr5-DTR-GFP, Apc, LSL-Notch (IC), and R26-reporter strains of mice. Some mice were given diphtheria toxin to ablate Lgr5-positive cells, were irradiated, or were given 5-fluorouracil, hydroxyurea, doxorubicin, or dextran sodium sulfate to induce intestinal or colonic tissue injury. In intestinal tissues, we analyzed the fate of progeny that expressed Bhlha15. We used microarrays and reverse-transcription PCR to analyze gene expression patterns in healthy and injured intestinal tissues and in tumors. We analyzed gene expression patterns in human colorectal tumors using The Cancer Genome Atlas data set.

Results: Bhlha15 identified Paneth cells and short-lived secretory precursors (including pre-Paneth label-retaining cells) located just above the ISC zone in the intestinal epithelium. Bhlha15 cells had no plasticity after loss of Lgr5-positive cells or irradiation. However, Bhlha15 secretory precursors started to supply the enterocyte lineage after doxorubicin-induced epithelial injury in a Notch-dependent manner. Sustained activation of Notch converts Bhlha15 secretory precursors to long-lived enterocyte progenitors. Administration of doxorubicin and expression of an activated form of Notch resulted in a gene expression pattern associated with enterocyte progenitors, whereas only sustained activation of Notch altered gene expression patterns in Bhlha15 precursors toward those of ISCs. Bhlha15 enterocyte progenitors with sustained activation of Notch formed intestinal tumors with serrated features in mice with disruption of Apc. In the colon, Bhlha15 marked secretory precursors that became stem-like, cancer-initiating cells after dextran sodium sulfate-induced injury, via activation of Src and YAP signaling. In analyses of human colorectal tumors, we associated activation of Notch with chromosome instability-type tumors with serrated features in the left colon.

Conclusions: In mice, we found that short-lived precursors can undergo permanent reprogramming by activation of Notch and YAP signaling. These cells could mediate tumor formation in addition to traditional ISCs.
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http://dx.doi.org/10.1053/j.gastro.2018.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409180PMC
March 2019

Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness.

Cancer Discov 2018 11 5;8(11):1458-1473. Epub 2018 Sep 5.

Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.

In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-;-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL-;LSL-;-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC. Subdiaphragmatic vagotomy or knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214763PMC
November 2018

β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.

Cancer Cell 2018 01 14;33(1):75-90.e7. Epub 2017 Dec 14.

Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. Electronic address:

Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras;LSL-Trp53;Pdx1-Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain-derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective β-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.
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http://dx.doi.org/10.1016/j.ccell.2017.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760435PMC
January 2018

Bone Marrow Myeloid Cells Regulate Myeloid-Biased Hematopoietic Stem Cells via a Histamine-Dependent Feedback Loop.

Cell Stem Cell 2017 Dec 30;21(6):747-760.e7. Epub 2017 Nov 30.

Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA; Department of Medicine, University of Western Ontario, London, ON N6A 5W9, Canada.

Myeloid-biased hematopoietic stem cells (MB-HSCs) play critical roles in recovery from injury, but little is known about how they are regulated within the bone marrow niche. Here we describe an auto-/paracrine physiologic circuit that controls quiescence of MB-HSCs and hematopoietic progenitors marked by histidine decarboxylase (Hdc). Committed Hdc myeloid cells lie in close anatomical proximity to MB-HSCs and produce histamine, which activates the H receptor on MB-HSCs to promote their quiescence and self-renewal. Depleting histamine-producing cells enforces cell cycle entry, induces loss of serial transplant capacity, and sensitizes animals to chemotherapeutic injury. Increasing demand for myeloid cells via lipopolysaccharide (LPS) treatment specifically recruits MB-HSCs and progenitors into the cell cycle; cycling MB-HSCs fail to revert into quiescence in the absence of histamine feedback, leading to their depletion, while an H agonist protects MB-HSCs from depletion after sepsis. Thus, histamine couples lineage-specific physiological demands to intrinsically primed MB-HSCs to enforce homeostasis.
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http://dx.doi.org/10.1016/j.stem.2017.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975960PMC
December 2017

Dclk1-expressing tuft cells: critical modulators of the intestinal niche?

Am J Physiol Gastrointest Liver Physiol 2017 Oct 6;313(4):G285-G299. Epub 2017 Jul 6.

II. Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany;

-expressing tuft cells constitute a unique intestinal epithelial lineage that is distinct from enterocytes, Paneth cells, goblet cells, and enteroendocrine cells. Tuft cells express taste-related receptors and distinct transcription factors and interact closely with the enteric nervous system, suggesting a chemosensory cell lineage. In addition, recent work has shown that tuft cells interact closely with cells of the immune system, with a critical role in the cellular regulatory network governing responses to luminal parasites. Importantly, ablation of tuft cells severely impairs epithelial proliferation and tissue regeneration after injury, implicating tuft cells in the modulation of epithelial stem/progenitor function. Finally, tuft cells expand during chronic inflammation and in preneoplastic tissues, suggesting a possible early role in inflammation-associated tumorigenesis. Hence, we outline and discuss emerging evidence that strongly supports tuft cells as key regulatory cells in the complex network of the intestinal microenvironment.
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http://dx.doi.org/10.1152/ajpgi.00073.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668570PMC
October 2017

Histidine decarboxylase (HDC)-expressing granulocytic myeloid cells induce and recruit Foxp3 regulatory T cells in murine colon cancer.

Oncoimmunology 2017;6(3):e1290034. Epub 2017 Feb 10.

Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.

The colorectal tumor microenvironment contains a diverse population of myeloid cells that are recruited and converted to immunosuppressive cells, thus facilitating tumor escape from immunoediting. We have identified a genetically and functionally distinct subset of dynamic bone marrow myeloid cells that are characterized by histidine decarboxylase (HDC) expression. Lineage tracing in Hdc-CreERT2;R26-LSL-tdTomato mice revealed that in homeostasis, there is a strong bias by HDC myeloid cells toward the CD11bLy6G granulocytic lineage, which was accelerated during azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colonic carcinogenesis. More importantly, HDC myeloid cells strongly promoted colonic tumorigenesis, and colon tumor progression was profoundly suppressed by diphtheria toxin A (DTA)-mediated depletion of HDC granulocytic myeloid cells. In addition, tumor infiltration by Foxp3 regulatory T cells (Tregs) was markedly impaired following HDC myeloid cell depletion. We identified an HDC myeloid-derived Cxcl13/Cxcr5 axis that mediated Foxp3 expression and Treg proliferation. Ablation of HDC myeloid cells or disruption of the Cxcl13/Cxcr5 axis by gene knockdown impaired the production and recruitment of Tregs. Cxcl13 induction of Foxp3 expression in Tregs during tumorigenesis was associated with Stat3 phosphorylation. Overall, HDC granulocytic myeloid cells affect CD8 T cells directly and indirectly through the modulation of Tregs and thus appear to play key roles in suppressing tumoricidal immunity.
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http://dx.doi.org/10.1080/2162402X.2017.1290034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384347PMC
February 2017

Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling.

Cancer Cell 2017 01 15;31(1):21-34. Epub 2016 Dec 15.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.

Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find that Dclk1 tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1 cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in an ACh muscarinic receptor-3 (M3R)-dependent manner, in part through suppression of yes-associated protein (YAP) function. This feedforward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention.
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http://dx.doi.org/10.1016/j.ccell.2016.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225031PMC
January 2017

Epithelial Dclk1+ cells are not neural crest derived.

Stem Cell Investig 2016 21;3:60. Epub 2016 Oct 21.

Division of Digestive and Liver Diseases, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.

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http://dx.doi.org/10.21037/sci.2016.10.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104577PMC
October 2016

Three-Dimensional Gastrointestinal Organoid Culture in Combination with Nerves or Fibroblasts: A Method to Characterize the Gastrointestinal Stem Cell Niche.

Stem Cells Int 2016 30;2016:3710836. Epub 2015 Nov 30.

II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 181675 München, Germany.

The gastrointestinal epithelium is characterized by a high turnover of cells and intestinal stem cells predominantly reside at the bottom of crypts and their progeny serve to maintain normal intestinal homeostasis. Accumulating evidence demonstrates the pivotal role of a niche surrounding intestinal stem cells in crypts, which consists of cellular and soluble components and creates an environment constantly influencing the fate of stem cells. Here we describe different 3D culture systems to culture gastrointestinal epithelium that should enable us to study the stem cell niche in vitro in the future: organoid culture and multilayered systems such as organotypic cell culture and culture of intestinal tissue fragments ex vivo. These methods mimic the in vivo situation in vitro by creating 3D culture conditions that reflect the physiological situation of intestinal crypts. Modifications of the composition of the culture media as well as coculturing epithelial organoids with previously described cellular components such as myofibroblasts, collagen, and neurons show the impact of the methods applied to investigate niche interactions in vitro. We further present a novel method to isolate labeled nerves from the enteric nervous system using Dclk1-CreGFP mice.
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http://dx.doi.org/10.1155/2016/3710836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677245PMC
December 2015

Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran.

Stroke 2011 Dec 13;42(12):3594-9. Epub 2011 Oct 13.

Department of Neurology, University Heidelberg, INF 400, 69120 Heidelberg, Germany.

Background And Purpose: Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth.

Methods: In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly. Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 μL), or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later.

Results: DE substantially prolonged tail vein bleeding time and ecarin clotting time for 4 hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first 3 hours on serial T2* MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective. Prevention of hematoma growth and reversal of tail vein bleeding time by PCC were dose-dependent.

Conclusions: The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies.
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http://dx.doi.org/10.1161/STROKEAHA.111.624650DOI Listing
December 2011

Comparison of humoral neuroinflammation and adhesion molecule expression in two models of experimental intracerebral hemorrhage.

Exp Transl Stroke Med 2011 Oct 3;3(1):11. Epub 2011 Oct 3.

Department of Neurology, University Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.

Background: Inflammatory cascades contribute to secondary injury after intracerebral hemorrhage (ICH) via humoral factors and cell-mediated cytotoxicity. Several experimental models were previously developed to analyze post-hemorrhagic neuroinflammation. However, neuroinflammatory markers have not been compared face-to-face between these models so far, and therefore, pathophysiological conclusions drawn from only one individual model may not be valid.

Methods: We compared neuroinflammatory pathways in the two most common murine models: striatal injection of autologous blood or collagenase. Expression of pro- and anti-inflammatory cytokines (IL-1, TNF-α, IFN-γ, IL-6, TGF-β and IL-10) as well adhesion molecule expression (VCAM-1, ICAM-1) was analyzed by RT-PCR at several time points after ICH induction. Outcome and physiological parameters were compared between the models.

Results: Both models induced a profound and dynamic increase in the expression of pro-inflammatory cytokines and adhesion molecules. However, blood injection resulted in significantly more pronounced alteration of these markers than collagenase injection. This difference was associated with worse outcome after blood injection compared to the collagenase model despite equal ICH volumes.

Conclusions: This is the first study performing a face-to-face comparison of neuroinflammatory pathways in the two most widely used murine ICH models, revealing substantial differences between the models. This discrepancies need to be taken into account in designing future studies employing experimental ICH models, especially when analyzing neuroinflammatory pathways and therapies.
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http://dx.doi.org/10.1186/2040-7378-3-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195108PMC
October 2011