SAT-395-Bone marrow-mesenchymal stem cells of cirrhosis patients show insulin resistance and bioenergetic exhaustion

Kumar, dhananajay; Maheshwari, Deepanshu; Shubham, Smriti; Nautiyal, Nidhi; Rooge, Sheetalnath; Anand, Lovkesh; Vyas, Ashish Kumar; Sharma, Shwetank; Maiwall, Rakhi; Mohanty, Sujata; Bihari, Chhagan; Kumar, Anupam; Sarin, Shiv Kumar

doi:10.1016/s0618-8278(19)31614-7

Cited by 2 publications

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“…Likewise, another study from our group revealed that BM-MSCs have insulin resistance and impaired bioenergetics in cirrhotic patients. 13 Genetic polymorphisms of CSF3R were not identified in this study, which indicates a limited role of CSF3R polymorphisms and G-CSF therapy-related responses in cirrhosis patients.…”

Section: Discussionmentioning

confidence: 55%

CEACAM-1 Induced CSF3-receptor Downregulation in Bone Marrow Associated With Refractory Neutropenia in Advanced Cirrhosis

Bihari

Baweja

Shasthry

et al. 2022

J Clin Transl Hepatol

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Background and Aims Cirrhosis patients exhibit cytopenia, and, at times refractory neutropenia to granulocyte colony-stimulating factor (G-CSF), which acts through the CSF3-receptor (CSF3R), and changes in CSF3R can affect the response. We conducted this study to assess the CSF3R status and its relevance in cirrhotic patients. Methods Cirrhotic patients ( n =127) and controls ( n =26) with clinically indicated bone marrow (BM) examination were studied. BM assessment was done by qRT-PCR and immunohistochemistry (IHC) for CSF3R . Circulating G-CSF, 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 in liver cirrhosis patients who received G-CSF for severe neutropenia. Results The mean age was 48.6±13.4 years, and 80.3% were men. Circulatory CSF3R reduction was noted with the advancement of cirrhosis, and confirmed by qRT-PCR and IHC in BM. CSF3R decline was related to decreased hematopoietic stem cells (HSCs) and downregulation of CSF3R in the remaining HSCs. Cocultures confirmed that CEACAM1 led to CSF3R downregulation in BM cells by possible lysosomal degradation. Baseline low peripheral blood-(PB)-CSF3R also predisposed development of infections on follow-up. Decreased CSF3R was also associated with nonresponse to exogenous G-CSF treatment of neutropenia. Conclusions Advanced liver cirrhosis was associated with low CSF3R and high CEACAM1 levels in the BM and circulation, making patients prone to infection and inadequate response to exogenous G-CSF.

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Section: Discussionmentioning

confidence: 55%

CEACAM-1 Induced CSF3-receptor Downregulation in Bone Marrow Associated With Refractory Neutropenia in Advanced Cirrhosis

Bihari

Baweja

Shasthry

et al. 2022

J Clin Transl Hepatol

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“…Likewise, another study from our group revealed that BM-MSCs have insulin resistance and impaired bioenergetics in cirrhotic patients. [21] The genetic polymorphisms of CSF3R were not identi ed in this study. It indicates a limited role of CSF3R polymorphisms and G-CSF therapy-related responses in cirrhosis patients.…”

Section: Discussionmentioning

confidence: 82%

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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SAT-395-Bone marrow-mesenchymal stem cells of cirrhosis patients show insulin resistance and bioenergetic exhaustion

Cited by 2 publications

References 0 publications

CEACAM-1 Induced CSF3-receptor Downregulation in Bone Marrow Associated With Refractory Neutropenia in Advanced Cirrhosis

CEACAM-1 Induced CSF3-receptor Downregulation in Bone Marrow Associated With Refractory Neutropenia in Advanced Cirrhosis

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

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