Reversal of experimental Laron Syndrome by xenotransplantation of microencapsulated porcine Sertoli cells

Luca, Giovanni; Calvitti, Mario; Mancuso, Francesca; Falabella, G.; Arato, Iva; Bellucci, Catia; List, Edward O.; Bellezza, Enrico; Angeli, Giovanni; Lilli, Cinzia; Bodo, Maria; Becchetti, Ennio; Kopchick, John J.; Cameron, Don F.; Baroni, Tiziano; Calafiore, Riccardo

doi:10.1016/j.jconrel.2012.08.028

Cited by 20 publications

(16 citation statements)

References 29 publications

(30 reference statements)

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“…hormone receptor) and reduced production of IGF-1, via the release into the circulation of IGF-1 by SeC. Interestingly, SeC-derived IGF-1 remained detectable in the serum of the treated mice up to one year after injection [113]. Similarly, a single i.p.…”

Section: Pre-clinical Studies Using Microencapsulated Secmentioning

confidence: 93%

“…A single i.p. injection of MC-SeC promoted body growth in a mouse model of the human Laron syndrome (dwarfism), characterized by mutations in GHR (growth Alginate-based microcapsules have shown long durability in terms of survival of the entrapped cells and have been used in rodents, dogs and monkeys [111][112][113][114]. Moreover, alginate-based microcapsules containing human pancreatic islets have been employed in clinical trials in which they were transplanted i.p.…”

Section: Pre-clinical Studies Using Microencapsulated Secmentioning

confidence: 99%

“…Additional trophic factors known to be secreted by SeC may also concur to the amelioration of dystrophic muscle morphology. As an example, it has been demonstrated that SeC secrete IGF-1 [113], which has an essential role in muscle growth during development and regeneration [124] suggesting a possible involvement of IGF-1 in improving muscle regeneration in MC-SeC-treated dystrophic mice (Figure 3).…”

Section: Conclusion and Remarksmentioning

confidence: 99%

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Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

Chiappalupi

Salvadori

Luca

et al. 2017

JFMK

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Duchenne muscular dystrophy (DMD) is a lethal X-linked pathology due to lack of dystrophin and characterized by progressive muscle degeneration, impaired locomotion and premature death. The chronic presence of inflammatory cells, fibrosis and fat deposition are hallmarks of DMD muscle tissue. Many different therapeutic approaches to DMD have been tested, including cell-based and gene-based approaches, exon skipping, induction of expression of the dystrophin paralogue, utrophin, and, most recently the application of the CASPR/Cas9 genome editing system. However, corticosteroid treatment remains the gold standard therapy, even if corticosteroids have shown multiple undesirable side effects. Sertoli cells (SeC) have long been known for their ability to produce immunomodulatory and trophic factors, and have been used in a plethora of experimental models of disease. Recently, microencapsulated porcine SeC (MC-SeC) injected intraperitoneally in dystrophic mice produced morphological and functional benefits in muscles thanks to their release into the circulation of anti-inflammatory factors and heregulin β1, a known inducer of utrophin expression, thus opening a new avenue in the treatment of DMD. In order to stress the potentiality of the use of MC-SeC in the treatment of DMD, here, we examine the principal therapeutic approaches to DMD, and the properties of SeC (either nude or encapsulated into alginate-based microcapsules) and their preclinical and clinical use. Finally, we discuss the potential and future development of this latter approach.Keywords: Duchenne muscular dystrophy; therapeutic approaches; Sertoli cell; muscle inflammation; myopathies; encapsulation; biomaterials Duchenne Muscular Dystrophy (DMD)Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy. Muscular dystrophies are a group of inherited muscle diseases characterized by mutations in specific genes and resulting in muscle degeneration, impaired locomotion and premature death [1,2]. DMD is an X-linked recessive pathology caused by mutations in the dystrophin gene (DMD) usually resulting in the complete absence of this protein. Dystrophin is an essential component of the dystrophin-associated protein complex (DAPC) at the sarcolemma, a complex that ensures the structural and functional integrity of the myofibers during contraction representing a mechanical link between the intracellular cytoskeleton and the extracellular matrix. Absence of dystrophin or other components of the DAPC compromises the integrity of the DAPC itself leading to a susceptibility of myofibers to degeneration

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Section: Pre-clinical Studies Using Microencapsulated Secmentioning

confidence: 93%

Section: Pre-clinical Studies Using Microencapsulated Secmentioning

confidence: 99%

Section: Conclusion and Remarksmentioning

confidence: 99%

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Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

Chiappalupi

Salvadori

Luca

et al. 2017

JFMK

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“…Other studies have shown that the immune privilege status of the testis is likely contributed mostly by biological factors (e.g., cytokines) secreted by Sertoli cells (or primary cultures of Sertoli cells, but not Sertoli cell line), making Sertoli cells a prime candidate to serve as immunosuppressive cells for allogeneic and also xenogeneic transplantation (Dufour, et al 2008, Dufour, et al 2004, Kaur, et al 2013, Kaur, et al 2014, Mital, et al 2010). In fact, recent studies have demonstrated successful long-term stability of Sertoli cell-based cell transplant therapy for several pathological conditions (Luca, et al 2013, Luca, et al 2015). In short, unlike other blood-tissue barriers which are conferred mostly by endothelial TJ-barrier of microvessels, BTB is constituted by coexisting TJ, basal ES and GJ, along with intermediate filament-based desmosome between adjacent Sertoli cells near the basement membrane in the epithelium of seminiferous tubules.…”

Section: Structure and Function Of The Blood-testis Barrier (Btb)mentioning

confidence: 99%

Regulation of blood–testis barrier by actin binding proteins and protein kinases

Li¹,

Tang²,

Cheng³

2016

Reproduction

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The blood-testis barrier (BTB) is an important ultrastructure in the testis since the onset of spermatogenesis coincides with the establishment of a functional barrier in rodents and humans. It is also noted that a delay in the assembly of a functional BTB following treatment of neonatal rats with drugs such as diethylstilbestrol or adjudin also delays the first wave of spermiation. While the BTB is one of the tightest blood-tissue barriers, it undergoes extensive remodeling, in particular at stage VIII of the epithelial cycle to facilitate the transport of preleptotene spermatocytes connected in clones across the immunological barrier. Without this timely transport of preleptotene spermatocytes derived from type B spermatogonia, meiosis will be arrested, causing aspermatogenesis. Yet the biology and regulation of the BTB remains largely unexplored since the morphological studies in the 1970s. Recent studies, however, have shed new light on the biology of the BTB. Herein, we critically evaluate some of these findings, illustrating that the Sertoli cell BTB is regulated by actin binding proteins (ABPs), likely supported by non-receptor protein kinases, to modulate the organization of actin microfilament bundles at the site. Furthermore, microtubule (MT)-based cytoskeleton is also working in concert with the actin-based cytoskeleton to confer BTB dynamics. This timely review provides an update on the unique biology and regulation of the BTB based on the latest findings in the field, focusing on the role of ABPs and non-receptor protein kinases.

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“…It was previously demonstrated that intraperitoneal transplantation of microencapsulated SCs into a stringent murine animal model of type 1 diabetes mellitus, did reverse the disease in the majority of the recipients [3]. In this issue, Professor Calafiore and his colleagues report that porcine pre-pubertal SCs (pSCs), encapsulated in barium alginate-based microcapsules (SCs-MCs), can successfully promote growth in the dwarf GHR−/− "Laron mouse" by secreting pig IGF-1 (pIGF-1) [4].…”

mentioning

confidence: 99%

A cell therapy-based cure of the Laron Syndrome

Park

2013

Journal of Controlled Release

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Reversal of experimental Laron Syndrome by xenotransplantation of microencapsulated porcine Sertoli cells

Cited by 20 publications

References 29 publications

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

Regulation of blood–testis barrier by actin binding proteins and protein kinases

A cell therapy-based cure of the Laron Syndrome

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