The influence of mesenchymal stem cells on the electrical activity of DRG neurons in experimental diabetic neuropathy

• Grant number: 17/26625-8
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): March 20, 2018
• Effective date (End): March 19, 2019
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Carlos Amilcar Parada
• Grantee: Jalile Garcia Schiavuzzo
• Supervisor: Adalberto Merighi
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Research place: Università degli Studi di Torino (UNITO), Italy
• Associated to the scholarship: 14/21962-8 - Study of the effect of intrathecal stem cells administration on a rat model of diabetic peripheral neropathy, BP.DR

Abstract

The Peripheral Diabetic Neuropathy (PDN) is a most common complication of diabetes, a metabolic disease with increasing incidence worldwide and with important social and economic effects, affecting around 126 million people in the world.The mechanisms underlying abnormal nociception in diabetes are unclear, although inflammatory cytokines were proved to play an important role in the development of neuropathic pain because induces several peripheral effects, including vasodilatation, increased vascular permeability, cell migration and pain. Abnormal excitability of primary sensory neurons plays an important role in neuropathic pain. Evidence has accumulated that abnormal excitability of primary sensory neurons may contribute to the exaggerated pain associated with diabetic neuropathy as well , in particular, it has been shown that Nav1.7 and Nav1.8 were over-expressed and the transient sodium current was increased significantly in small dorsal root ganglion (DRG) neurons in streptozotocin (STZ)-induced diabetic rats .Recent studies also show that Mesenchymal stem cells (MSCs) could be a new therapy target to treat diabetic neuropathyc pain, in fact MSC treatment reduced hyperalgesia in diabetic neuropathy ratsMesenchymal stem cells (MSCs) are multipotent stromal cells that exist in many tissues and are capable of differentiating into several different cell types. Under certain experimental conditions exogenously administered MSCs migrate to damaged tissue sites, where they participate in tissue repair. Therefore, the therapeutic effects of MSCs may depend largely on the capacity of MSCs to regulate inflammation and tissue homeostasis via an array of immunosuppressive factors, cytokines, growth factors and differentiation factors, their communication with the inflammatory microenvironment is an essential part of this process, and the cellular and molecular mechanisms of the interaction between MSCs and various participants in inflammation has as such TnF-±, prostaglandin E2, IL-1 and IL-10. Although the therapeutic effects of MSCs may depend on the capacity of MSCs to regulate inflammation studies show that cultures of neurons of diabetic rats, incubated with Tnf-± increase the Nav 1.7 channels ( Galloway C. et al., 2013) therefore, the effect of MSC on the control of diabetic neuropathic pain can occur through the modulation of the exitability of these channels in DRG neurons.Voltage-gated Na+ channels are essential for the initiation and propagation of action potentials in excitable cells. Since the expression of functional Nav. subunits is an essential hallmark of neuronal differentiation and crucial for signal transmission in the nervous system, Na+ channel activity can be used as an electrophysiological readout for neuronal maturation of differentiating ES cells toward functional neurons (Kevin R. et al.,2015)Several studies have investigated the expression of Na+ channels in stem cells and differentiating cells , some investigations have found that Na+ channel activity is important for differentiation and maturation of neuronal cells.However, this work intends to investigate whether stem cells promote changes in the electrical activity of DRG neurons of rodents with STZ-induced diabetic neuropathy. In particular we will focus on Nav1.7 and Nav1.8 that are over-expressed in small DRG neurons of STZ-induced diabetic rats, and also to investigate if the intrathecal treatment with MSCs induces the release neurotrophic growth factors and potentially supplements with specific cell types required for vascular or neuron regeneration in DRGs. Also to compare the anatomical differences between cell of groups of neurons.The overall purpose of the current study is thus to elucidate the contribution of MSCs in DRG neurons in restoring a normal neuronal activity which may, in turn, alleviate the symptoms of PDN in rodents.