Dysfunctions of Human Muscle Stem Cells in Sepsis

Study Overview
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Brief Summary
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Severe critical illness is often complicated by Intensive Care Unit - Acquired Weakness (ICU-AW), which is associated with increased in and post-ICU mortality, with delayed weaning from mechanical ventilation and with long-term functional. Several mechanisms have been incriminated in the pathophysiology of ICU-AW, but muscle regeneration has not been well investigated in this context, even though its involvement is suggested by the protracted functional consequences of ICU-AW. Recent data suggest that muscle regeneration could be impaired after sepsis, and that Mesenchymal Stem Cells (MSCs) treatment could improve the post-injury muscle recovery.

Detailed Description
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Severe critical illness is often complicated by Intensive Care Unit - Acquired Weakness (ICU-AW), which is clinically characterized by bilateral and symmetrical limb weakness and is related to a myopathy and/or axonal polyneuropathy. ICU-AW affects between 25% to 60% mechanically ventilated patients more than 7 days and is associated with increased in and post-ICU mortality, with delayed weaning from mechanical ventilation and with long-term functional disability. Most patients who develop an ICU-AW have been admitted for a sepsis episode and the main risk factors of ICU-AW include the severity of critical illness, immobilization, hyperglycemia and the use of some medications including steroids and neuromuscular agents, although this is somewhat controversial. The pathophysiology of critical illness myopathy is thought to involve the following mechanisms: 1) impairment of muscular membrane excitability, secondary to an dysregulation of sodium channel gating, 2) mitochondrial dysfunction leading to bioenergetic failure and oxidative stress and 3) proteolysis, mainly related an activation of the ubiquitin-proteasome pathway. These mechanisms can be triggered by various factors, notably systemic inflammatory mediators, endocrine dysfunction, immobilization, some drugs and electrolyte disturbances. The protracted functional consequences of ICU-AW indicate that muscle regeneration is also impaired. Surprisingly, muscle regeneration, which essentially depends on the muscle stem cells (also called satellite cells), has not been well investigated in the context of critical illness. The satellite cells (SC), that are located at the periphery of the muscle fiber, are activated in response to any muscle injury and then proliferate and differentiate to repair or replace the damaged fibers, but also self-renew to replenish the muscle stem cells reservoir. It was recently demonstrated in a murine model of polymicrobial peritonitis that SC activation, proliferation and expression of myogenic markers were impaired after sepsis, leading to an impaired muscle regeneration, but that post-sepsis intramuscular administration of exogenous Mesenchymal Stem Cells (MSCs) could reverse this SC dysfunction. MSC treatment significantly improved the post-injury muscle recovery with decreasing necrosis and fibrosis but also increased the force of isolated single fibers. The objectives of this translational research are to identify the mechanisms of Human SC dysfunction in patients with severe sepsis, to describe in vitro the effects of MSCs on this SC dysfunction, and to study hematopoietic cells and their damage in the blood and muscle consecutively to a sepsis, and their interaction with muscle stem cells.

Official Title
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Dysfunctions of Human Muscle Stem Cells in Sepsis

Conditions
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Sepsis

Intervention / Treatment
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* Procedure: Human biological samples


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Affiliated or beneficiary of a social security system Informed consent to research : Consent from patient, Or consent from patient and close relative, Or non-objection from family for biological sample donation for research. Population 1 (sepsis) : Patients hospitalized in Intensive Care Unit, with intra-abdominal sepsis requiring emergency surgery. Population 2 (inflammatory condition with or without sepsis) : Brain dead patients scheduled for multi organ retrieval (2a) ; Patients with refractory cariogenic shock and requiring surgery for assistance with (2b). Population 3 (control) : Patients scheduled for intra-abdominal surgery. Exclusion Criteria: Patient with preexisting neuromuscular disease Under 18 year-old Pregnancy..

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with and without sepsis<br>Patients with sepsis, Patients with inflammatory disease without sepsis, Patients without inflammatory disease without sepsis. Human biological samples collected for research : Blood sample Muscle biopsy Bone marrow sample (mesenchymal stem cells) | Procedure: Human biological samples<br>* Blood sample - Muscle biopsy - Bone marrow sample (mesenchymal stem cells)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle regenerative capacities | The muscle regenerative capacity after sepsis would be assessed by the presence of anisocytosis, the proportion of small atrophic fibers, the proportion of endomysial fibrosis of the total muscle section area and the presence of calcified necrotic myofibers. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Satellite cell dysfunction after sepsis | Number of satellite cells (SC) Proportion of cells actively cycling Capacity of SC to differentiate into myofibers | 3 years | 
| Regenerative capacities of Human satellite cells in presence of mesenchymal stem cells | Number of satellite cells (SC) Proportion of cells actively cycling Capacity of SC to differentiate into myofibers | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intensive Care Unit - Acquired Weakness (ICU-AW)