Use of Sertoli cells to treat DMD patients is supported by their immunomodulatory rather than immunosuppressive effect

Sertoli cells (SeC) are the major component of the seminiferous tubules in the testes, where they secrete a plethora of trophic and immunomodulatory factors necessary for development of germ cells and to protect developing germ cells against the immune system attack, respectively. Naked or encapsulated SeC have been widely used as a therapeutic approach to many pre-clinical studies [1,2]. A single intraperitoneal (i.p.) injection of microencapsulated porcine SeC (SeC-MC) translated into recovery of muscle morphology and performance in dystrophic (mdx) mice in the absence of pharmacological immunosuppression, thanks to a double SeC effect, i.e., an antiinflammatory action and heregulin beta 1-dependent induction of utrophin at the sarcolemma [3]. This opened a new route of treatment for Duchenne muscular dystrophy (DMD) patients. However, it is still debating if SeC exert immunomodulatory or immunosuppressive effects, which is of relevance in view of their application in humans. Here we show that mice previously injected i.p. with SeC-MC were more able to solve pulmonary infection by Aspergillus fumigatus, one of the most common species causing disease in immunodeficient individuals, compared to control mice injected with empty microcapsules (E-MC), as evaluated by analysis of bronchoalveolar lavage, fungal growth, histology (PAS and Grocott staining), and inflammatory chemokines and cytokines expression (RT-PCR) in lungs. Moreover, mice previously injected i.p. with SeC-MC and later injected subcutaneously with LLC (Lewis lung carcinoma) cells showed similar tumor growth over time to mice injected with E-MC, further suggesting that SeC do not exert an immunosuppressive role. This was also confirmed by the observation that one year from i.p. injection SeC-MC-injected mdx mice did not show neither adverse effects nor increased incidence of tumor formation. Altogether, our data suggest that SeC exert immunomodulatory rather than immunosuppressive effect, further supporting the use of i.p. injection of SeC-MC as a potential treatment of DMD patients and diseases characterized by an inflammatory or autoimmunity environment. [1] Luca et al. (2018) Sertoli cells for cell transplantation: preclinical studies and future perspectives. Andrology 6:385-95 [2] Chiappalupi et al. (2017) Employment of microencapsulated Sertoli cells as a new tool to treat Duchenne muscular dystrophy. J. Funct. Morphol. Kinesiol. 2(4):47 [3] Chiappalupi et al. (2016) Intraperitoneal injection of microencapsulated Sertoli cells restores muscle morphology and performance in dystrophic mice. Biomaterials 75:313-26