Dysfunctions of Human Muscle Stem Cells in Sepsis

Sepsis Clinical Trial

— DISCUSS  

Official title:

Dysfunctions of Human Muscle Stem Cells in Sepsis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02789995
• Other study ID #: 2015-015
• Secondary ID: ID-RCB number :
• Status: Completed
• Phase: N/A
• Start date: June 23, 2016
• Est. completion date: June 28, 2018

Study information

• Verified date: October 2019
• Source: Institut Pasteur
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 93
• Est. completion date: June 28, 2018
• Est. primary completion date: June 28, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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..

Related Conditions & MeSH terms

• Sepsis
• Toxemia

Intervention

Procedure:
• Human biological samples
Blood sample - Muscle biopsy - Bone marrow sample (mesenchymal stem cells)

Locations

Country	Name	City	State
France	Hopital Henri Mondor, Service de Réanimation chirurgicale polyvalente	Créteil
France	Hôpital Pitié Salpêtrière, Anesthésie et Réanimation, Institut de Cardiologie	Paris
France	Hôpital Pitié Salpétrière, Salle de surveillance post-interventionnelle, Accueil des Polytraumatisés	Paris
France	Hôpital Pitié Salpêtrière, Service de Chirurgie Générale, Viscérale et Endocrinienne	Paris
France	Hôpital Pitié Salpêtrière, Service de Chirurgie Hépatobiliaire et de Transplantation Hépatique	Paris
France	Hôpital Pitié Salpêtrière, Service de réanimation chirurgicale polyvalente	Paris
France	Hôpital Saint-Antoine, Département d'Anesthésie-réanimation	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Institut Pasteur

Country where clinical trial is conducted

France, 

References & Publications (1)

Rocheteau P, Chatre L, Briand D, Mebarki M, Jouvion G, Bardon J, Crochemore C, Serrani P, Lecci PP, Latil M, Matot B, Carlier PG, Latronico N, Huchet C, Lafoux A, Sharshar T, Ricchetti M, Chrétien F. Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy. Nat Commun. 2015 Dec 15;6:10145. doi: 10.1038/ncomms10145. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Satellite cell dysfunction after sepsis	Number of satellite cells (SC); Proportion of cells actively cycling; Capacity of SC to differentiate into myofibers	3 years
Secondary	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