Lack of PKCθ Promotes Regenerative Ability of Muscle Stem Cells in Chronic Muscle Injury

Fiore, Piera Filomena; Benedetti, A.; Sandonà, Martina; Madaro, Luca; Bardi, Marco De; Saccone, Valentina; Puri, Pier Lorenzo; Gargioli, Cesare; Lozanoska-Ochser, Biliana; Bouché, Marina

doi:10.3390/ijms21030932

Cited by 14 publications

(15 citation statements)

References 38 publications

(53 reference statements)

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“…Frozen heart ventricles were cut into 8 μm sections and stored at −20 °C until use. Histochemistry and immunofluorescence analyses were performed as previously described [ 35 , 36 ]. Briefly, for histological analysis, the sections were stained with hematoxylin/eosin or with Sirius red/picric acid (both from Sigma-Aldrich, St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

Accelerating the Mdx Heart Histo-Pathology through Physical Exercise

Morroni

Schirone

Vecchio

et al. 2021

Life

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Chronic cardiac muscle inflammation and fibrosis are key features of Duchenne Muscular Dystrophy (DMD). Around 90% of 18-year-old patients already show signs of DMD-related cardiomyopathy, and cardiac failure is rising as the main cause of death among DMD patients. The evaluation of novel therapies for the treatment of dystrophic heart problems depends on the availability of animal models that closely mirror the human pathology. The widely used DMD animal model, the mdx mouse, presents a milder cardiac pathology compared to humans, with a late onset, which precludes large-scale and reliable studies. In this study, we used an exercise protocol to accelerate and worsen the cardiac pathology in mdx mice. The mice were subjected to a 1 h-long running session on a treadmill, at moderate speed, twice a week for 8 weeks. We demonstrate that subjecting young mdx mice (4-week-old) to “endurance” exercise accelerates heart pathology progression, as shown by early fibrosis deposition, increases necrosis and inflammation, and reduces heart function compared to controls. We believe that our exercised mdx model represents an easily reproducible and useful tool to study the molecular and cellular networks involved in dystrophic heart alterations, as well as to evaluate novel therapeutic strategies aimed at ameliorating dystrophic heart pathology.

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Section: Methodsmentioning

confidence: 99%

Accelerating the Mdx Heart Histo-Pathology through Physical Exercise

Morroni

Schirone

Vecchio

et al. 2021

Life

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“…This beneficial effect was mainly due to the inhibition of PKCθ in T cells, which leads to reduced inflammation [10][11][12]. Interestingly, we also found that lack of PKCθ promotes muscle repair in dystrophic mice, even at advanced stages of the disease, supporting SCs survival and maintenance [13]. However, whether this effect was due to reduced inflammation or to a direct role of PKCθ on SCs activity, or both, was still unclear.…”

Section: Introductionmentioning

confidence: 53%

Targeting PKCθ Promotes Satellite Cell Self-Renewal

Benedetti

Fiore

Madaro

et al. 2020

IJMS

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Skeletal muscle regeneration following injury depends on the ability of satellite cells (SCs) to proliferate, self-renew, and eventually differentiate. The factors that regulate the process of self-renewal are poorly understood. In this study we examined the role of PKCθ in SC self-renewal and differentiation. We show that PKCθ is expressed in SCs, and its active form is localized to the chromosomes, centrosomes, and midbody during mitosis. Lack of PKCθ promotes SC symmetric self-renewal division by regulating Pard3 polarity protein localization, without affecting the overall proliferation rate. Genetic ablation of PKCθ or its pharmacological inhibition in vivo did not affect SC number in healthy muscle. By contrast, after induction of muscle injury, lack or inhibition of PKCθ resulted in a significant expansion of the quiescent SC pool. Finally, we show that lack of PKCθ does not alter the inflammatory milieu after acute injury in muscle, suggesting that the enhanced self-renewal ability of SCs in PKCθ-/- mice is not due to an alteration in the inflammatory milieu. Together, these results suggest that PKCθ plays an important role in SC self-renewal by stimulating their expansion through symmetric division, and it may represent a promising target to manipulate satellite cell self-renewal in pathological conditions.

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“…Acute muscle injury was induced the day before SC transplantation. To induce muscle injury tibialis muscles were injected with 0.01 ml of Cardiotoxin from Naja Pallida (10 μM) (Latoxan ZA, Les Auréats, Fr), using a 30 Gauge micro-syringe [23][24][25][26].…”

Section: Sc Transplantationmentioning

confidence: 99%

A novel approach for the isolation and long-term expansion of pure satellite cells based on ice-cold treatment

et al. 2021

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Satellite cells (SCs) are muscle stem cells capable of regenerating injured muscle. The study of their functional potential depends on the availability of methods for the isolation and expansion of pure SCs with preserved myogenic properties after serial passages in vitro. Here, we describe the ice-cold treatment (ICT) method, which is a simple, economical, and efficient method for the isolation and in vitro expansion of highly pure mouse and human SCs. It involves a brief (15–30 min) incubation on ice (0 °C) of a dish containing a heterogeneous mix of adherent muscle mononuclear cells, which leads to the detachment of only the SCs, and gives rise to cultures of superior purity compared to other commonly used isolation methods. The ICT method doubles up as a gentle passaging technique, allowing SC expansion over extended periods of time without compromising their proliferation and differentiation potential. Moreover, SCs isolated and expanded using the ICT method are capable of regenerating injured muscle in vivo. The ICT method involves minimal cell manipulation, does not require any expertise or expensive reagents, it is fast, and highly reproducible, and greatly reduces the number of animals or human biopsies required in order to obtain sufficient number of SCs. The cost-effectiveness, accessibility, and technical simplicity of this method, as well as its remarkable efficiency, will no doubt accelerate SC basic and translational research bringing their therapeutic use closer to the clinic.

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Lack of PKCθ Promotes Regenerative Ability of Muscle Stem Cells in Chronic Muscle Injury

Cited by 14 publications

References 38 publications

Accelerating the Mdx Heart Histo-Pathology through Physical Exercise

Accelerating the Mdx Heart Histo-Pathology through Physical Exercise

Targeting PKCθ Promotes Satellite Cell Self-Renewal

A novel approach for the isolation and long-term expansion of pure satellite cells based on ice-cold treatment

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