Embryonic stem cell-derived mesenchymal stem cells alleviate skeletal muscle injury induced by acute compartment syndrome

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Abstract

Background

Acute compartment syndrome (ACS), a well-known complication of musculoskeletal injury, results in muscle necrosis and cell death. Embryonic stem cell-derived mesenchymal stem cells (ESC-MSCs) have been shown to be a promising therapy for ACS. However, their effectiveness and potentially protective mechanism remain unknown. The present study was designed to investigate the efficacy and underlying mechanism of ESC-MSCs in ACS-induced skeletal muscle injury.

Method

A total of 168 male Sprague–Dawley (SD) rats underwent 2 h of intracompartmental pressure elevation by saline infusion into the anterior compartment of the left hindlimb to establish the ACS model. ESC-MSCs were differentiated from the human embryonic stem cell (ESC) line H9. A dose of 1.2 × 10 ⁶ of ESC-MSCs was intravenously injected during fasciotomy. Post-ACS assessments included skeletal edema index, serum indicators, histological analysis, apoptosis, fibrosis, regeneration, and functional recovery of skeletal muscle. Then, fluorescence microscopy was used to observe the distribution of labeled ESC-MSCs in vivo, and western blotting and immunofluorescence analyses were performed to examine macrophages infiltration in skeletal muscle. Finally, we used liposomal clodronate to deplete macrophages and reassess skeletal muscle injury in response to ESC-MSC therapy.

Result

ESC-MSCs significantly reduced systemic inflammatory responses, ACS-induced skeletal muscle edema, and cell apoptosis. In addition, ESC-MSCs inhibited skeletal muscle fibrosis and increased regeneration and functional recovery of skeletal muscle after ACS. The beneficial effects of ESC-MSCs on ACS-induced skeletal muscle injury were accompanied by a decrease in CD86-positive M1 macrophage polarization and an increase in CD206-positive M2 macrophage polarization. After depleting macrophages with liposomal clodronate, the beneficial effects of ESC-MSCs were attenuated.

Conclusion

Our findings suggest that embryonic stem cell-derived mesenchymal stem cells infusion could effectively alleviate ACS-induced skeletal muscle injury, in which the beneficial effects were related to the regulation of macrophages polarization.

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Most cited references 47

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Embryonic stem cell lines derived from human blastocysts.

J. A. Thomson, J. Itskovitz-Eldor, S Shapiro … (1998)

Human blastocyst-derived, pluripotent cell lines are described that have normal karyotypes, express high levels of telomerase activity, and express cell surface markers that characterize primate embryonic stem cells but do not characterize other early lineages. After undifferentiated proliferation in vitro for 4 to 5 months, these cells still maintained the developmental potential to form trophoblast and derivatives of all three embryonic germ layers, including gut epithelium (endoderm); cartilage, bone, smooth muscle, and striated muscle (mesoderm); and neural epithelium, embryonic ganglia, and stratified squamous epithelium (ectoderm). These cell lines should be useful in human developmental biology, drug discovery, and transplantation medicine.

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Current Mechanistic Concepts in Ischemia and Reperfusion Injury.

GIOU-TENG YIANG, Meng-Yu Wu, Andy Tsai … (2018)

Ischemia-reperfusion injury is associated with serious clinical manifestations, including myocardial hibernation, acute heart failure, cerebral dysfunction, gastrointestinal dysfunction, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. Ischemia-reperfusion injury is a critical medical condition that poses an important therapeutic challenge for physicians. In this review article, we present recent advances focusing on the basic pathophysiology of ischemia-reperfusion injury, especially the involvement of reactive oxygen species and cell death pathways. The involvement of the NADPH oxidase system, nitric oxide synthase system, and xanthine oxidase system are also described. When the blood supply is re-established after prolonged ischemia, local inflammation and ROS production increase, leading to secondary injury. Cell damage induced by prolonged ischemia-reperfusion injury may lead to apoptosis, autophagy, necrosis, and necroptosis. We highlight the latest mechanistic insights into reperfusion-injury-induced cell death via these different processes. The interlinked signaling pathways of cell death could offer new targets for therapeutic approaches. Treatment approaches for ischemia-reperfusion injury are also reviewed. We believe that understanding the pathophysiology ischemia-reperfusion injury will enable the development of novel treatment interventions.

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Myocardial ischaemia–reperfusion injury and cardioprotection in perspective

Gerd Heusch (2020)

Despite the increasing use and success of interventional coronary reperfusion strategies, morbidity and mortality from acute myocardial infarction are still substantial. Myocardial infarct size is a major determinant of prognosis in these patients. Therefore, cardioprotective strategies aim to reduce infarct size. However, a perplexing gap exists between the many preclinical studies reporting infarct size reduction with mechanical and pharmacological interventions and the poor translation into better clinical outcomes in patients. This Review revisits the pathophysiology of myocardial ischaemia-reperfusion injury, including the role of autophagy and forms of cell death such as necrosis, apoptosis, necroptosis and pyroptosis. Other cellular compartments in addition to cardiomyocytes are addressed, notably the coronary microcirculation. Preclinical and clinical research developments in mechanical and pharmacological approaches to induce cardioprotection, and their signal transduction pathways, are discussed. Additive cardioprotective interventions are advocated. For clinical translation into treatments for patients with acute myocardial infarction, who typically are of advanced age, have comorbidities and are receiving several medications, not only infarct size reduction but also attenuation of coronary microvascular obstruction, as well as longer-term targets including infarct repair and reverse remodelling, must be considered to improve patient outcomes. Future clinical trials must focus on patients who really need adjunct cardioprotection, that is, those with severe haemodynamic alterations.

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Author and article information

Contributors

Mao Zhang: z2jzk@zju.edu.cn

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 15 July 2022

Publication date PMC-release: 15 July 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 313

Affiliations

[1 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Emergency Medicine, Second Affiliated Hospital, , Zhejiang University School of Medicine, ; No. 88 Jiefang Road, Hangzhou, 310009 China

[2 ]Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou, China

[3 ]Zhejiang Provincial Clinical Research Center for Emergency and Critical Care Medicine, Hangzhou, China

Article

Publisher ID: 3000

DOI: 10.1186/s13287-022-03000-0

PMC ID: 9284828

PubMed ID: 35841081

SO-VID: 3149ff46-b9e6-4ae2-8488-900da0a1a939

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 9 February 2022

Date accepted : 14 May 2022

Funding

Funded by: Natural Science Foundation of China

Award ID: 82072126

Award Recipient : Mao Zhang

Funded by: Zhejiang Provincial Key Research and Development Program of China

Award ID: 2021C03073

Award Recipient : Mao Zhang

Funded by: FundRef http://dx.doi.org/10.13039/501100013058, Jiangsu Provincial Key Research and Development Program;

Award ID: 2021C03036

Award Recipient : Mao Zhang

Funded by: The Key Program Cosponsored by Zhejiang Province and National Health Commission of China

Award ID: WKJ-ZJ-2207

Award Recipient : Mao Zhang

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: acute compartment syndrome,skeletal muscle injury,embryonic stem cells,mesenchymal stem cells,macrophages

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: acute compartment syndrome, skeletal muscle injury, embryonic stem cells, mesenchymal stem cells, macrophages

Embryonic stem cell-derived mesenchymal stem cells alleviate skeletal muscle injury induced by acute compartment syndrome

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Abstract

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Bacterial extracellular vesicles

Most cited references 47

Embryonic stem cell lines derived from human blastocysts.

Current Mechanistic Concepts in Ischemia and Reperfusion Injury.

Myocardial ischaemia–reperfusion injury and cardioprotection in perspective

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Contributors

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