Sertoli Cells Avert Neuroinflammation-Induced Cell Death and Improve Motor Function and Striatal Atrophy in Rat Model of Huntington Disease

Background and Aim : Huntington’s disease (HD) is a heritable disorder, genetically instigated by insertion mutation of huntingtin gene (Htt), linked with continuing cell loss and degeneration mostly in the striatum and neocortex (Bates et al. 2014; Leegwater-Kim and Cha 2004; MacDonald et al. 1993). Currently, cell therapy approaches in HD have essentially been focused on replenishing or shielding cells lost over the period of the disease (Clelland et al. 2008). Sertoli cells (SCs) as the nurturing cells are located within seminiferous tubules of the testis and provide an immunoprivileged milieu for the growing spermatogonia. SCs have been demonstrated to locally immunoprotect co-implanted cells (Shamekh et al. 2006; Korbutt et al. 1997; Sanberg et al. 1996; Suarez-Pinzon et al. 2000; Yang et al. 2002; Willing et al. 1999a), improve cell proliferation and neuronal induction (Shamekh et al. 2008; Hemendinger et al. 2005), and survive for prolonged periods of time once grafted (Dufour et al. 2008). Prior works have implemented isolated SCs for the remedy of diseases in animal models, namely diabetes and Parkinson’s disease (PD) (Suarez-Pinzon et al. 2000; Willing et al. 1999a). Moreover, SCs are capable of secretion of plenty of immunoregulatory and trophic factors including Fas (CD95) ligand (FasL), transforming growth factors (TGF-α and TGF-β), interleukin 1α (IL-1α) and interleukin 6 (IL-6), platelet-derived growth factor (PDGF), and neurturin (NTN) (Piccirillo et al. 1998; Griswold 1993; Skinner 1993; Gnessi et al. 1995; French et al. 1996; Widenfalk et al. 1997; Cudicini et al. 1997; Sanberg et al. 1997b; O’Bryan et al. 2005). Regarding the central nervous system, SCs grafted into the brain and spinal cord could deliver compounds with trophic and anti-inflammatory effects on the neighboring environment.The current study was designed to investigate the in vitro and in vivo efficacy of primary rat SCs and their paracrine effect against oxidative stress with emphasis on HD.Methods : SCs were isolated and immunophenotypically characterized by positive expression of GATA4. Besides, synthesis of neurotrophic factors of glial cell-derived neurotrophic factor and VEGF by SCs were proved. Next, PC12 cells were exposed to hydrogen peroxide in the presence of conditioned media (CM) collected from SC (SC-CM) and cell viability and neuritogenesis were determined. Bilateral striatal implantation of SC in 3-nitropropionic acid (3-NP)-lesioned rat models was performed, and 1 month later, post-graft analysis was doneResults : According to our in vitro results, the CM of SC protected PC12 cells against oxidative stress and remarkably augmented cell viability and neurite outgrowth. Moreover, grafted SCs survived, exhibited decreases in both gliosis and inflammatory cytokine levels, and ameliorated motor coordination and muscle activity, together with an increase in striatal volume as well as in dendritic length of the striatum in HD ratsConclusion : In conclusion, our results indicate that SCs provide a supportive environment, with potential therapeutic benefits aimed at HD.

کلیدواژه ها:

Transplantation ، Huntington ، Striatum ، Sertoli cells