RESUMEN
Hemopoietic stem cells (HSCs) are extrinsically controlled by the bone marrow (BM) microenvironment. Mice devoid of the extracellular matrix molecule Tenascin-C (TNC) were reported to develop normally. The current study explores the relationship between TNC and hemopoiesis, from HSCs within their niche to maturing progenitors in alternate niches. Although the absence of TNC did not alter the size of the BM stem cell pool, we report decreased thymic T cell progenitors with redistribution to other lymphoid organs, suggesting an anchoring role for TNC. TNC did not play an essential role in stem and progenitor cell homing to BM, but significantly altered lymphoid primed progenitor cell homing. These cells express the TNC receptor, integrin α9ß1, with the same reduced homing evident in the absence of this integrin. The absence of TNC also resulted in an increased proportion and number of mature circulating T cells. In addition, the absence of TNC significantly impaired hemopoietic reconstitution after transplant and increased stem and progenitor cell mobilization. In summary, our analysis revealed unidentified roles for TNC in hemopoiesis: in lineage commitment of thymic T cell progenitors, peripheral T cell migration, and hemopoietic reconstitution.
Asunto(s)
Hematopoyesis/fisiología , Células Progenitoras Linfoides/citología , Tenascina/metabolismo , Animales , Animales Modificados Genéticamente , Linaje de la Célula/genética , Citometría de Flujo , Hematopoyesis/genética , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Linfocitos T/citología , Tenascina/genéticaRESUMEN
A large body of evidence suggests hemopoietic stem cells (HSCs) exist in an endosteal niche close to bone, whereas others suggest that the HSC niche is intimately associated with vasculature. In this study, we show that transplanted hemopoietic stem and progenitor cells (HSPCs) home preferentially to the trabecular-rich metaphysis of the femurs in nonablated mice at all time points from 15 minutes to 15 hours after transplantation. Within this region, they exist in an endosteal niche in close association with blood vessels. The preferential homing of HSPCs to the metaphysis occurs rapidly after transplantation, suggesting that blood vessels within this region may express a unique repertoire of endothelial adhesive molecules. One candidate is hyaluronan (HA), which is highly expressed on the blood vessel endothelium in the metaphysis. Analysis of the early stages of homing and the spatial dis-tribution of transplanted HSPCs at the single-cell level in mice devoid of Has3-synthesized HA, provides evidence for a previously undescribed role for HA expressed on endothelial cells in directing the homing of HSPCs to the metaphysis.
Asunto(s)
Vasos Sanguíneos/citología , Médula Ósea/irrigación sanguínea , Huesos/citología , Células Madre Hematopoyéticas/citología , Animales , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/ultraestructura , Huesos/metabolismo , Moléculas de Adhesión Celular/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Femenino , Fémur/citología , Fémur/metabolismo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Hialuronano Sintasas , Ácido Hialurónico/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Nicho de Células Madre/irrigación sanguínea , Nicho de Células Madre/citología , Migración Transendotelial y Transepitelial , Microtomografía por Rayos XRESUMEN
A variety of techniques have been applied to investigate the interrelationship between age-related atrophy of rat soleus muscle and other signs of muscle aging, such as changes in muscle fibre type composition, decrease in bioenergy capacity and accumulation of mitochondrial DNA (mtDNA) arrangements. Age-related atrophy of rat soleus muscle was shown to start at the age of about 28 months. It was accompanied by a decrease in the number of slow twitch muscle fibres (type I) and an increase in the proportion of muscle fibres co-expressing slow and fast myosins (type Ic and IIc fibres). Bioenergy capacity of the soleus muscle, assessed by the level of measurable cytochrome c oxidase (COX) activity, was found to be decreased both in the middle age and old rats compared to the young animals. Muscle atrophy was also accompanied by a decrease in the amount of full-length mitochondrial DNA (FL-mtDNA) amplifiable by the extra-long PCR (XL-PCR) and the increase in the number of mtDNA deletions. The results of the study show that the decline in the bioenergy capacity of the rat soleus occurs by the middle age. It is followed by the onset of the age-related muscle atrophy that is accompanied by both fibre type changes and functional mtDNA degradation.