No description available.

Thesis (Ph. D. in Biomedical Engineering)--Vanderbilt University, Aug. 2007. / Title from title screen. Includes bibliographical references.

Promoting tissue repair in adults represents a major unmet medical need. Tissue regeneration relies on the activation of quiescent endogenous stem cells and whilst considerable progress has been made, novel therapies based on stem cells have thus far failed to translate to routine clinical practice. Much attention has focussed on administrating exogenous stem cells expanded or altered in vitro. However, this approach faces several major limitations, including poor engraftment, high cost and importantly, the necessity for immunosuppression for allogenic cells. An alternative strategy that overcomes these shortcomings is to promote repair by harnessing the regenerative potential of endogenous stem cells. This thesis focussed on the role of alarmins, the upstream group of mediators released immediately following injury, in promoting tissue regeneration. I show that the alarmin HMGB1 accelerates tissue regeneration in various systems by transitioning multiple stem cell types from the quiescent G₀ to the G_Alert state. Firstly, in vitro screening of candidate alarmins with human bone marrow-derived mesenchymal stromal cells showed that only pre-treatment with HMGB1 improved osteogenic differentiation. Using an optimised murine fracture model, I found that local administration of HMGB1 accelerated bone regeneration via the CXCL12-CXCR4 axis, whilst healing was impaired in inducible Hmgb1^-/- animals. Cell cycle analyses revealed that HMGB1 transitioned the skeletal stem cell from G₀ to G_Alert. In this intermediate phase, the cell is more metabolically active and efficiently enters the cell cycle when exposed to activating factors. This effect also extended to other types of stem cells, including murine haematopoietic and muscle stem cells, as well as human haematopoietic stem and progenitor cells, and MSCs. Using murine models, HMGB1 accelerated recovery from injury to these tissues. Finally, treatment with a single systemic dose of HMGB1 two weeks before injury also accelerated bone, haematopoietic, and muscle regeneration, which was indicative of an acquired pro-regenerative signature. These findings document that the HMGB1-G_Alert pathway results in a dynamic and adaptive multi-tissue regenerative response, and suggest that exogenous HMGB1 may be of therapeutic benefit in diverse clinical contexts, including trauma, chemotherapy, and elective surgery.

O contato com as cerdas da lagarta de Premolis semirufa (Pararama) desperta sintomas da inflamação aguda e nos indivíduos poliacidentados pode causar deformidades comuns às sinovites crônicas (pararamose). No presente estudo foi mostrado que o extrato das cerdas da lagarta apresenta intensa atividade proteolítica, sendo capaz de ativar o Sistema Complemento, promover hidrólise de C3, C4 e C5 e a geração de anafilatoxinas. Análises cromatográficas do extrato permitiram o isolamento de uma serinoprotease de 82 kDa capaz de promover tais atividades. Em modelo murino, foi verificado que o extrato é capaz de induzir altos títulos de anticorpos, pronunciada reação inflamatória, ativação de linfócitos T e APCs, bem como produção de citocinas pró-inflamatórias. Os dados obtidos demonstram a existência, no extrato das cerdas da pararama, de várias enzimas que podem atuar em conjunto na geração e desenvolvimento das manifestações clínicas da pararamose. / The contact with the Premolis semirufas caterpillar bristles (Pararama) causes symptoms of the acute inflammation and, in the individuals after multiple accidents, joint deformities common to chronic synovitis (pararamose) can occur. In the current study it was shown that caterpillar bristles extract has intense proteolytic activity, being able to activate the Complement System, induce cleavage of C3, C4 and C5, and the generation of anaphylatoxins. Chromatographic analysis of the extract allowed the isolation of a serine protease with Mr of 82 kDa able to promote such activities. In murine model, it was demonstrated that the extract is able to induce high antibody titers, a pronounced inflammatory reaction, activation of T lymphocytes and APCs, as well as the generation of proinflammatory cytokines. The data obtained demonstrate the existence, in the pararama bristles extract, of numerous enzymes that can act together in the generation and development of clinical manifestations of pararamose.

Diss. (sammanfattning) Linköping : Univ., 2001. / Härtill 4 uppsatser.

O contato com as cerdas da lagarta de Premolis semirufa (Pararama) desperta sintomas da inflamação aguda e nos indivíduos poliacidentados pode causar deformidades comuns às sinovites crônicas (pararamose). No presente estudo foi mostrado que o extrato das cerdas da lagarta apresenta intensa atividade proteolítica, sendo capaz de ativar o Sistema Complemento, promover hidrólise de C3, C4 e C5 e a geração de anafilatoxinas. Análises cromatográficas do extrato permitiram o isolamento de uma serinoprotease de 82 kDa capaz de promover tais atividades. Em modelo murino, foi verificado que o extrato é capaz de induzir altos títulos de anticorpos, pronunciada reação inflamatória, ativação de linfócitos T e APCs, bem como produção de citocinas pró-inflamatórias. Os dados obtidos demonstram a existência, no extrato das cerdas da pararama, de várias enzimas que podem atuar em conjunto na geração e desenvolvimento das manifestações clínicas da pararamose. / The contact with the Premolis semirufas caterpillar bristles (Pararama) causes symptoms of the acute inflammation and, in the individuals after multiple accidents, joint deformities common to chronic synovitis (pararamose) can occur. In the current study it was shown that caterpillar bristles extract has intense proteolytic activity, being able to activate the Complement System, induce cleavage of C3, C4 and C5, and the generation of anaphylatoxins. Chromatographic analysis of the extract allowed the isolation of a serine protease with Mr of 82 kDa able to promote such activities. In murine model, it was demonstrated that the extract is able to induce high antibody titers, a pronounced inflammatory reaction, activation of T lymphocytes and APCs, as well as the generation of proinflammatory cytokines. The data obtained demonstrate the existence, in the pararama bristles extract, of numerous enzymes that can act together in the generation and development of clinical manifestations of pararamose.