Laminin-111 protein therapy reduces muscle pathology and improves viability of a mouse model of merosin-deficient congenital muscular dystrophy.

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a lethal muscle-wasting disease that is caused by mutations in the LAMA2 gene, resulting in the loss of laminin-α2 protein. MDC1A patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance, and have reduced life expectancy. There are currently no effective treatments or cures for MDC1A. Laminin-α2 is required for the formation of heterotrimeric laminin-211 (ie, α2, ß1, and γ1) and laminin-221 (ie, α2, ß2, and γ1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (ie, α1, ß1, and γ1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-α2-deficient muscle but is absent from adult skeletal muscle. In this study, we determined whether treatment with Engelbreth-Holm-Swarm-derived mouse laminin-111 protein could rescue MDC1A in the dy(W-/-) mouse model. We demonstrate that laminin-111 protein systemically delivered to the muscles of laminin-α2-deficient mice prevents muscle pathology, improves muscle strength, and dramatically increases life expectancy. Laminin-111 also prevented apoptosis in laminin-α2-deficient mouse muscle and primary human MDC1A myogenic cells, which indicates a conserved mechanism of action and cross-reactivity between species. Our results demonstrate that laminin-111 can serve as an effective protein substitution therapy for the treatment of muscular dystrophy in the dy(W-/-) mouse model and establish the potential for its use in the treatment of MDC1A.

Role of substrates in diabetes therapy: stem cell differentiation and islet transplantation.

Type 1 diabetes affects more than a million people in the United States and many more across the world. While pharmaceutical interventions and insulin supplementation are the most commonplace treatment of diabetes, these are not essentially cures and can potentially lead to long-term complications. Transplantation of insulin-producing Islets of Langerhans from donor pancreas has been established as a promising alternative to diabetes therapy. While successful islet transplantation has the potential of providing a cure, the primary hurdles to be overcome for it to be clinically viable are the scarcity of donor islets and immune rejection of transplanted islets. Recent advances in stem cell culture and differentiation techniques have established stem cells as a likely source of transplantable islets. Different stem cell sources have been induced toward pancreatic differentiation using specific chemical perturbations along with use of specific substrates. An approach to overcoming the second hurdle of immune rejection of transplantable islets is to encapsulate the islets in specific biomaterials. In this review, we discuss the extensive use of various substrates for pancreatic differentiation of different stem cell sources, along with different biomaterial designs used for islet transplantation.

Development of a nerve scaffold using a tendon chitosan tube.

Bridge grafting (15 mm) into the sciatic nerve of SD rats was carried out using tendon chitosan tubes having either a circular or triangular cross-section, as well as triangular tubes combined with laminin, CDPGYIGSR, or CSRARKQAASIKVAVSAD (n = 15 in each group). As a control, isografting (15 mm) was carried out in the SD rats (n = 7). Specimens were taken after 1, 2, 4, 6, and 8 weeks for histology, and nerve regeneration was evaluated electro-physiologically and histologically after 12 weeks. The mechanical strength of triangular tubes was found to be higher than circular tubes, and the inner volume of a triangular tube tends to be larger than in circular tubes. Nerve tissue regeneration along the tube wall was found in both the laminin and laminin peptide groups. According to the result of percentage neural tissue in relation to evoked action potentials, the consecutive treatments of YIGSR and IKVAV was found to match the effectiveness of intact laminin.