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the science- SERTOLI CEll TRANSPLANTATION

Focus on Sertoli Cells have been recognized to play an important role at different levels, including regulation of synthesis of androgen binding protein (ABP) and the paracrine action on peritubular and Leydig cells. In addition, SCs provide an appropriate microenvironment for the development of germ cells, while recent reports have shown that these cells may provide nutrients and immuno-modulatory and trophic factors that are able to ameliorate survival and development of different cell types and to improve their functional competence. In particular, in Type 1 Diabetes (T1DM) murine models, SCs protected co-grafted allogeneic and xenogeneic islets from immune destruction. Hence, SCs might confer the transplanted islets immunoprotection, thus representing a possible approach to overcome a major obstacle associated with cell therapy. Finally, our team has recently demonstrated that SCs, enveloped in barium alginate-based microcapsules and transplanted in peritoneal cavity of pre-diabetic and diabetic NOD’s, can prevent/or reverse T1DM, based on SCs powerful immuno-modulatory effects and ß-cell regeneration properties.

Microencapsulated Sertoli cells : A NEW PRODUCT FOR CELL AND MOLECULAR THERAPY OF TYPE 1 DIABETES MELLITUS AND OTHER AUTOIMMUNE DISEASES. Sertoli cells (SCs), originally situated in the testis, produce nutrients and trophic factors that are necessary for normal germ cell lineage development and maturation (from spermatogonia stem cells to mature spermatozoa), while immuno-protecting these cells by means of secreted immuno-modulatory factors.

Isolated allo and xenogeneic SCs, which may uniquely prevent immune attack by themselves, have been used for years in cell transplantation protocols to immuno-protect “bystander” cells in experimental animal models (Emerich et al., 2003).

Because transplanted “naked” SCs would be impossible to retrieve, thereby disregarding an important regulatory issue (as per FDA’s guidelines – see www.fda.org), we have employed our original and patented technology for fabrication of ultrapure alginate-based microcapsules (MCs) to envelop pure populations of isolated pre-pubertal pig SC (pSCs). .

PRODUCT APPLICATIONS 1) THERAPY OF TYPE 1 DIABETES We have shown in our paper (Fallarino et al., 2009), that our PSCs-MCs are competent at eliciting functional pancreatic islets in severely diabetic NOD mice, reversing disease, inducing a stable reversion of the diabetic state in a remarkably high percentage of recipient hosts (81%) (Fig.2).

Our results have clearly demonstrated that PSCs-MCs can reverse experimental T1DM both modulating NOD mice immune system and inducing a generation of newly formed islets, accompanied by an ability of the islets to produce insulin, glucagon, and somatostatin. All together, these unique findings might open new research frontiers, based on SCs-MCs grafts for the cure of T1DM.

Fig.2 Blood glucose concentrations in three NOD recipients successfully treated with PSCs-MCs

2) THERAPY OF LARON SYNDROME The Laron mouse is the best animal model of the Laron syndrome, an orphan disease with 300 patients reported so far worldwide, hallmarked by a severe dwarfism. This condition relates to genetically-induced, defective production of insulin-like growth factor I (IGF-I) one of the main secretory products of Sertoli cells). In an attempt to cure the experimental counterpart of the human disease, we transplanted Laron mice with PSCs-MCs by a simple intra-peritoneal injection. The treated animals showed a 30% mean body weight (b.w.) increase as compared to untreated controls. Moreover, b.w. increased proportionally and harmoniously with other body organs and tissues, as confirmed by weight measurements of each individual retrieved organ (liver, spleen, kidney, heart, lungs and thymus), by the end of the experiment, demonstrating significant difference in single organ weight between PSCs-MCs-treated mice and control untreated Laron mice (NLM). Additionally, the mean value of the nose-anus length increased by 9% in the PSCs-MCs-treated mice which was significantly greater than one seen in the untreated controls.

The differences in growth between pSC-MCs-treated and control mice were evident at the gross inspection (Fig. 3). The work has now been submitted for publication in a top ranked Journal.

Fig. 3. Figure illustrates a visible difference in growth between age-matched control NLM (left side) and PSCs-MCs treated (right side) mice.

3) SKIN ALLOGRAFT We have demonstrated (Bistoni et al., 2012, Biomaterials, in press) that rats treated with PSCs-MCs tolerated skin grafts significantly longer than control rats, while lymphocytic infiltration was not observed in 82% of the rats grafted with the alginate microcapsules containing PSCs. Histological staining with hematoxylin/eosin showed, in the control rats (Fig. 4B and D), lymphocyte infiltration in comparison with the PSCs-MCs treated animals (Fig. 4A and C). These showed absence or reduction of lymphocytic infiltration at the graft site.

Fig. 4. Effects of pSC-MCs (A, C) and control (B, D) on tissue samples stained with Hematoxylin-eosin (H&E).

Legend: 1 donor derma, 2 recipient tissue, grafting zone, abundant lymphocytic infiltration.

Other experimental trials with graft of micro-encapsulated PSCs are being conducted at this time, with respect to

4) EXPERIMENTAL CROHN DISEASE (University of Georgia)

5) AUTOIMMUNE ENCEPHALOMYELITIS (Neuromed Institute, Venafro, Italy)

6) MUSCULAR DYSTROPHY The study has been conducted mainly at the University of Perugia along with some studies at (University of Rome “La Sapienza”, Rome, Italy),(Duchenne)