Early cirrhosis and a preserved bone marrow niche favour regenerative response to growth factors in decompensated cirrhosis

Anand, Lovkesh; Bihari, Chhagan; Kedarisetty, Chandan Kumar; Rooge, Sheetalnath; Kumar, Divyesh; Shubham, Smriti; Kumar, Guresh; Sahney, Amrish; Sharma, Manoj Kumar; Maiwall, Rakhi; Kumar, Anupam; Sarin, Shiv Kumar

doi:10.1111/liv.13923

Cited by 27 publications

(24 citation statements)

References 34 publications

(69 reference statements)

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“…Strong conclusions cannot be made from the data in the Kedarisetty et al 47 study on survival benefits with GCSF due to the absence of a GCSF-only treatment arm. Similar findings were echoed in the study by Anand et al 55 The authors showed that addition of erythropoietin to GCSF led to better regenerative response than GCSF monotherapy in patients with low MELD score (<16). The need for regenerative cell therapy in patients with low MELD scores and relatively lower mortality rates in the short-and intermediate-term remain debatable in the absence of quality long-term effects with such experimental treatments.…”

Section: Critical Appraisal Of Gcsf In Decompensated Cirrhosissupporting

confidence: 76%

Role of Granulocyte Colony-stimulating Factor Therapy in Cirrhosis, ‘Inside Any Deep Asking Is the Answering’

Philips¹,

Augustine²,

Ahamed³

et al. 2019

Journal of Clinical and Translational Hepatology

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Liver cirrhosis progresses through multiple clinical stages which culminate in either death or liver transplantation. Availability of organs, timely listing and prompt receipt of donor-livers pose difficulties in improving transplant-listed and transplant outcomes. In this regard, regenerative therapies, particularly with granulocyte colony-stimulating factor (GCSF), has become a lucrative option for improving transplant-free survival. However, the literature is confusing with regards to patient selection and real outcomes. In this exhaustive review, we describe the basics of liver fibrosis and cirrhosis through novel insights from a therapeutic point of view, discuss preclinical studies on GCSF in advanced liver disease to improve on clinical utility, shed light on the pertinent literature of GCSF in advanced cirrhosis, and provide astute inputs on growth factor therapy in decompensated cirrhosis.

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Section: Critical Appraisal Of Gcsf In Decompensated Cirrhosissupporting

confidence: 76%

Role of Granulocyte Colony-stimulating Factor Therapy in Cirrhosis, ‘Inside Any Deep Asking Is the Answering’

Philips¹,

Augustine²,

Ahamed³

et al. 2019

Journal of Clinical and Translational Hepatology

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“…1. One cohort (n=22) represents those cirrhotic patients who received G-CSF therapy in previous study [11] and where stored BM and peripheral blood plasma samples were available (retrospective). The response was considered if there is a reduction of CTP>1 and/or MELD>2 as described [14].…”

Section: Phase-1 Study Participants and Methodsmentioning

confidence: 99%

“…[9,10] A study from our group revealed that those with early cirrhosis and su cient BM reserve could respond to GCSF. [11] Another concern with the progressive stages of cirrhosis is severe cytopenia, including neutropenia.…”

Section: Introductionmentioning

confidence: 99%

CSF3-Receptor Downregulation in Bone Marrow contributes to Ineffectiveness of GCSF in Advanced Liver Cirrhosis

Bihari

Baweja

Lal

et al. 2021

Preprint

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Introduction: Cirrhosis patients exhibit cytopenia and variable response to GCSF, with benefits in early cirrhosis. GCSF acts through the CSF3-receptor (CSF3R), and changes in CSF3R can affect the response. We investigated the possible mechanism for the lack of efficacy of GCSF in advanced cirrhosisMethodsCirrhotic patients (n = 127) and controls (n = 26) who underwent clinically indicated bone marrow (BM) examination were studied. BMs were assessed for RNA sequencing, qRT-PCR, and immunohistochemistry (IHC) for CSF3R and associated genes. Circulating GCSF, CSF3R, and carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) were measured. BM hematopoietic precursor cells and their alterations were examined by flow cytometry. The findings were validated, where the GCSF was administered as for liver regeneration (n = 22) and severe neutropenia (n = 15)ResultsThe mean age was 48.6 ± 13.4 years, 80.3% males. Gene set enrichment analysis showed lowered CSF3R in Child's C compared to A, confirmed by qRT-PCR and IHC. Circulatory CSF3R was also reduced in advanced cirrhosis. CSF3R decline was related to decrease hematopoietic stem cells (HSCs) and downregulation of CSF3R in remaining HSCs. CSF3R inhibitory protein CEACAM1 caused CSF3R downregulation. CEACAM-1, in turn, positively correlated with the increased lysosomal expression in HSCs. Peripheral blood-CSF3R was lesser in those cases who developed an infection Baseline CSF3R was also lower in G-CSF non-responders.ConclusionsCSF3R is downregulated in patients with advanced cirrhosis, and it could be the underlying cause of the inadequate response to GCSF.

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“…82 There was an increase in osteoblasts, decrease in neo-vascularization, and an increase in percentage of CD34þ BMSCs in these patients post-G-CSF therapy, suggesting a potential effect of G-CSF in improving bonemarrow response in cirrhosis supporting enhanced hepatic regeneration. 83 Altogether, G-CSF holds the promise of ameliorating gut-derived infection and inflammation, improving bone-marrow and hepatic regeneration process; the major targets for reversal in patients with AH.…”

Section: Effects Of G-csf On Bone Marrowmentioning

confidence: 99%

Insights into the Role of Granulocyte Colony-Stimulating Factor in Severe Alcoholic Hepatitis

2021

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Alcohol use disorder is the predominant cause of chronic liver disease globally. The standard of care for the treatment of alcoholic hepatitis, corticosteroids, has been shown to provide a therapeutic response in ∼60% of carefully selected patients with a short-term survival benefit. The patients who do not respond to steroids, or are ineligible due to infections or very severe disease, have little options other than liver transplantation. There is, thus, a large unmet need for new therapeutic strategies for this large and sick group of patients. Granulocyte colony stimulating factor (G-CSF) has been shown to favorably modulate the intrahepatic immune milieu and stimulate the regenerative potential of the liver. Initial studies have shown encouraging results with G-CSF in patients with severe alcoholic hepatitis. It has also been found to help steroid nonresponsive patients. There is, however, a need for careful selection of patients, regular dose monitoring and close observation for adverse events of G-CSF. In this review, we analyze the basis of the potential benefits, clinical studies, cautions and challenges in the use of G-CSF in alcoholic hepatitis.

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Early cirrhosis and a preserved bone marrow niche favour regenerative response to growth factors in decompensated cirrhosis

Abstract: Early DC (MELD < 16) patients with mild-moderate ascites and those with a healthy cellular baseline BM respond better to growth factor therapy. Addition of EPO to G-CSF provides better regenerative response than G-CSF monotherapy.

Cited by 27 publications

References 34 publications

Role of Granulocyte Colony-stimulating Factor Therapy in Cirrhosis, ‘Inside Any Deep Asking Is the Answering’

Role of Granulocyte Colony-stimulating Factor Therapy in Cirrhosis, ‘Inside Any Deep Asking Is the Answering’

CSF3-Receptor Downregulation in Bone Marrow contributes to Ineffectiveness of GCSF in Advanced Liver Cirrhosis

Insights into the Role of Granulocyte Colony-Stimulating Factor in Severe Alcoholic Hepatitis

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