RESUMEN
CD34 is a highly glycosylated sialomucin expressed on a variety of cells, ranging from vascular endothelial cells to haematopoietic stem cells. Depending on its glycosylation state, CD34 has been shown to promote or inhibit cell adhesion and migration; however, a functional role for CD34 in the gut has not been determined. Using a model of Salmonella-induced gastroenteritis, we investigated the role of CD34 in the context of infection. Upon oral infection, the number of CD34+ cells detected in the submucosa, vascular endothelium and lamina propria significantly increased in S. Typhimurium-infected C57Bl/6 mice. The pathology of S. Typhimurium-infected C57Bl/6 mice was characterized by recruitment of neutrophils to the site of inflammation, submucosal oedema and crypt destruction. In contrast, Cd34(-/-) mice showed a delayed pathology, a defect in inflammatory cell migration into the intestinal tissue and enhanced survival. Importantly, this was not due to a lack of chemotactic signals in Cd34(-/-) mice as these mice had either similar or significantly higher levels of pro-inflammatory cytokines and chemokines post infection when compared with infected C57/Bl6 control mice. In summary, we demonstrate a novel role for CD34 in enhancing migration of inflammatory cells and thereby exacerbating host-mediated immunopathology in the intestine of S. Typhimurium-infected mice.
Asunto(s)
Antígenos CD34/inmunología , Ciego/inmunología , Ciego/patología , Gastroenteritis/inmunología , Salmonelosis Animal/inmunología , Salmonella typhimurium , Animales , Antígenos CD34/metabolismo , Adhesión Celular , Movimiento Celular , Quimiocinas/inmunología , Edema , Endotelio Vascular/inmunología , Gastroenteritis/microbiología , Gastroenteritis/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila , Salmonelosis Animal/microbiología , Salmonelosis Animal/patologíaRESUMEN
Efficient tissue regeneration is dependent on the coordinated responses of multiple cell types. Here, we describe a new subpopulation of fibro/adipogenic progenitors (FAPs) resident in muscle tissue but arising from a distinct developmental lineage. Transplantation of purified FAPs results in the generation of ectopic white fat when delivered subcutaneously or intramuscularly in a model of fatty infiltration, but not in healthy muscle, suggesting that the environment controls their engraftment. These cells are quiescent in intact muscle but proliferate efficiently in response to damage. FAPs do not generate myofibres, but enhance the rate of differentiation of primary myogenic progenitors in co-cultivation experiments. In summary, FAPs expand upon damage to provide a transient source of pro-differentiation signals for proliferating myogenic progenitors.
Asunto(s)
Adipocitos/citología , Desarrollo de Músculos/fisiología , Fibras Musculares Esqueléticas/citología , Músculo Esquelético/lesiones , Células Madre/citología , Adipocitos/metabolismo , Animales , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Proliferación Celular , Células Cultivadas , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Desarrollo de Músculos/genética , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Mioblastos/citología , Mioblastos/metabolismo , Trasplante de Células Madre , Células Madre/metabolismoRESUMEN
Sca-1 (Stem Cell Antigen-1) is a member of the Ly-6 family proteins that functions in cell growth, differentiation, and self-renewal in multiple tissues. In skeletal muscle Sca-1 negatively regulates myoblast proliferation and differentiation, and may function in the maintenance of progenitor cells. We investigated the role of Sca-1 in skeletal muscle regeneration and show here that Sca-1 expression is upregulated in a subset of myogenic cells upon muscle injury. We demonstrate that extract from crushed muscle upregulates Sca-1 expression in myoblasts in vitro, and that this effect is reversible and independent of cell proliferation. Sca-1(-/-) mice exhibit defects in muscle regeneration, with the development of fibrosis following injury. Sca-1(-/-) muscle displays reduced activity of matrix metalloproteinases, critical regulators of extracellular matrix remodeling. Interestingly, we show that the number of satellite cells is similar in wild-type and Sca-1(-/-) muscle, suggesting that in satellite cells Sca-1 does not play a role in self-renewal. We hypothesize that Sca-1 upregulates, directly or indirectly, the activity of matrix metalloproteinases, leading to matrix breakdown and efficient muscle regeneration. Further elucidation of the role of Sca-1 in matrix remodeling may aid in the development of novel therapeutic strategies for the treatment of fibrotic diseases.
Asunto(s)
Antígenos Ly/fisiología , Matriz Extracelular/metabolismo , Proteínas de la Membrana/fisiología , Músculo Esquelético/fisiología , Mioblastos/fisiología , Regeneración/fisiología , Animales , Proliferación Celular , Células Cultivadas , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Regulación hacia Arriba/fisiologíaRESUMEN
The molecular mechanisms that direct the migration of early T lymphocyte progenitors to the thymus are unknown. We show here that P-selectin is expressed by thymic endothelium and that lymphoid progenitors in bone marrow and thymus bind P-selectin. Parabiosis, competitive thymus reconstitution and short-term homing assays indicated that P-selectin and its ligand PSGL-1 are functionally important components of the thymic homing process. Accordingly, thymi of mice lacking PSGL-1 contained fewer early thymic progenitors and had increased empty niches for prothymocytes compared with wild-type mice. Furthermore, the number of resident thymic progenitors controls thymic expression of P-selectin, suggesting that regulation of P-selectin expression by a thymic 'niche occupancy sensor' may be used to direct progenitor access.