Mesenchymal Stromal Cell-Based Therapies as Promising Treatments for Muscle Regeneration After Snakebite Envenoming

Abstract

Snakebite envenoming is a global neglected disease with an incidence of up to 2.7 million new cases every year. Although antivenoms are so-far the most effective treatment to reverse the acute systemic effects induced by snakebite envenoming, they have a limited therapeutic potential, being unable to completely neutralize the local venom effects. Local damage, such as dermonecrosis and myonecrosis, can lead to permanent sequelae with physical, social, and psychological implications. The strong inflammatory process induced by snake venoms is associated with poor tissue regeneration, in particular the lack of or reduced skeletal muscle regeneration. Mesenchymal stromal cells (MSCs)-based therapies have shown both anti-inflammatory and pro-regenerative properties. We postulate that using allogeneic MSCs or their cell-free products can induce skeletal muscle regeneration in snakebite victims, improving all the three steps of the skeletal muscle regeneration process, mainly by anti-inflammatory activity, paracrine effects, neovascularization induction, and inhibition of tissue damage, instrumental for microenvironment remodeling and regeneration. Since snakebite envenoming occurs mainly in areas with poor healthcare, we enlist the principles and potential of MSCs-based therapies and discuss regulatory issues, good manufacturing practices, transportation, storage, and related-procedures that could allow the administration of these therapies, looking forward to a safe and cost-effective treatment for a so far unsolved and neglected health problem.

Intramuscular Bleeding and Formation of Microthrombi during Skeletal Muscle Damage Caused by a Snake Venom Metalloprotease and a Cardiotoxin

“…SVMPs are crucial components in viper venom-induced myotoxicity due to their ability to hinder adequate muscle regeneration and complete functional recovery following acute damage [ 25 ]. The proteolytic activity of these toxins causes important alterations to different components of the muscle architecture, especially the ECM, which is essential for muscle regeneration [ 4 , 11 ]. CAMP was previously reported to damage the ECM in skeletal muscle [ 11 ].…”

“…SBE has been classified as a high-priority neglected tropical disease by the World Health Organisation (WHO) and causes around 150,000 deaths and 500,000 permanent disabilities worldwide every year [ 3 ]. Venom-induced skeletal muscle damage is a key factor of SBE-induced permanent disabilities [ 4 ]. Antivenoms are generally not beneficial in treating and preventing SBE-induced muscle damage as the large immunoglobulin molecules are unable to penetrate the damaged local tissues [ 5 , 6 ].…”

The Search for Natural and Synthetic Inhibitors That Would Complement Antivenoms as Therapeutics for Snakebite Envenoming

“…Furthermore, therapeutic interventions may be directed towards improving the regenerative capacity of affected tissues and cells. This is the case of NUCC-390, an agonist of CXCR 4 receptor, which promotes the regeneration of nerve terminals affected by neurotoxic PLA 2 s that act presynaptically [ 115 ], or possible therapies to improve skeletal muscle regeneration after venom-induced myonecrosis [ 116 , 117 ]. Hence, the in depth understanding of venom composition, the mechanisms of action of the most relevant toxins, and the pathophysiology of envenomings will provide valuable information not only for the design of specific toxin inhibitors, but also for other interventions aimed at controlling endogenous pathways playing a role in envenoming.…”

Differential effects of the venoms of Russell’s viper and Indian cobra on human myoblasts

“…The current understanding of the pathogenesis of SBE-induced myonecrosis points out that the individual and/or synergistic actions of venom toxins directly or indirectly contribute to this process 9 . Notably, the differential expression of key toxins in elapid (e.g.…”