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1.
Biomaterials ; 33(3): 751-61, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22019120

RESUMO

Herein we describe a bio-inspired, affinity binding alginate-sulfate scaffold, designed for the presentation and sustained release of transforming growth factor beta 1 (TGF-ß1), and examine its effects on the chondrogenesis of human mesenchymal stem cells (hMSCs). When attached to matrix via affinity interactions with alginate sulfate, TGF-ß1 loading was significantly greater and its initial release from the scaffold was attenuated compared to its burst release (>90%) from scaffolds lacking alginate-sulfate. The sustained TGF-ß1 release was further supported by the prolonged activation (14 d) of Smad-dependent (Smad2) and Smad-independent (ERK1/2) signaling pathways in the seeded hMSCs. Such presentation of TGF-ß1 led to hMSC chondrogenic differentiation; differentiated chondrocytes with deposited collagen type II were seen within three weeks of in vitro hMSC seeding. By contrast, in scaffolds lacking alginate-sulfate, the effect of TGF-ß1 was short-term and hMSCs could not reach a similar differentiation degree. When hMSC constructs were subcutaneously implanted in nude mice, chondrocytes with deposited type II collagen and aggrecan typical of the articular cartilage were found in the TGF-ß1 affinity-bound constructs. Our results highlight the fundamental importance of appropriate factor presentation to its biological activity, namely - inducing efficient stem cell differentiation.


Assuntos
Condrogênese/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Alicerces Teciduais/química , Fator de Crescimento Transformador beta/química , Alginatos/química , Animais , Western Blotting , Células Cultivadas , Eletroforese em Gel de Poliacrilamida , Feminino , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Humanos , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Nus , Proteína Smad2/metabolismo , Engenharia Tecidual/métodos , Fator de Crescimento Transformador beta/farmacologia
2.
Biomaterials ; 31(35): 9273-84, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20869768

RESUMO

Engineering of cell-based constructs for treating a variety of immune-related diseases by local transplantation of the cells in a pre-designed matrix is an emerging therapeutic approach, which can potentially reduce the side effects associated with systemic cell injection. Stromal cells have been shown to exert immunosuppressive properties and thus can be exploited for autoimmune regulation and cell transplantation. Here, we demonstrate the fabrication of a stromal cell-based construct, which serves as a lymphoid-like organ with immune regulatory characteristics. In the proposed system, stromal cells are co-seeded with dendritic cells (DC) in a macro-porous alginate scaffold containing the encephalitogenic myelin-derived peptide, proteolipid protein (PLP). We demonstrate that the presence of stromal cells attenuates DC maturation upon lipopolysaccharide stimulus. In vitro, we show that while the migration of pathogenic PLP-specific T cells to construct cultivated with or without stromal cells does not differ, their activation and proliferation are significantly suppressed in the presence of stromal cells. Upon in vivo transplantation, under the kidney capsule of mice, the pathogenic activation and proliferation of T cells which were drawn into the construct were suppressed in the co-seeded constructs. This system thus serves as a lymphoid-like organ with regulatory characteristics, which can be applied for local tolerance induction, for application in cell transplantations as well as autoimmune diseases.


Assuntos
Células Estromais/imunologia , Alginatos/química , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Citometria de Fluxo , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Tolerância Imunológica/efeitos dos fármacos , Imuno-Histoquímica , Lipopolissacarídeos/farmacologia , Camundongos , Proteína Proteolipídica de Mielina/química , Proteína Proteolipídica de Mielina/imunologia , Células Estromais/citologia , Alicerces Teciduais/química
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