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Murine spleen tissue regeneration from neonatal spleen capsule requires lymphotoxin priming of stromal cells.

ABSTRACT: Spleen is a tissue with regenerative capacity, which allows autotransplantation of human spleen fragments to counteract the effects of splenectomy. We now reveal in a murine model that transplant of neonatal spleen capsule alone leads to the regeneration of full spleen tissue. This finding indicates that graft-derived spleen stromal cells, but not lymphocytes, are essential components of tissue neogenesis, a finding verified by transplant and regeneration of Rag1KO spleen capsules. We further demonstrate that lymphotoxin and lymphoid tissue inducer cells participate in two key elements of spleen neogenesis, bulk tissue regeneration and white pulp organization, identifying a lymphotoxin-dependent pathway for neonatal spleen regeneration that contrasts with previously defined lymphotoxin-independent embryonic spleen organogenesis.

SUBMITTER: Tan JK

PROVIDER: S-EPMC4105237 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Murine spleen tissue regeneration from neonatal spleen capsule requires lymphotoxin priming of stromal cells.

Tan Jonathan K H JK Watanabe Takeshi T

Journal of immunology (Baltimore, Md. : 1950) 20140620 3

Spleen is a tissue with regenerative capacity, which allows autotransplantation of human spleen fragments to counteract the effects of splenectomy. We now reveal in a murine model that transplant of neonatal spleen capsule alone leads to the regeneration of full spleen tissue. This finding indicates that graft-derived spleen stromal cells, but not lymphocytes, are essential components of tissue neogenesis, a finding verified by transplant and regeneration of Rag1KO spleen capsules. We further de ...[more]

PMID: 24951816

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Project description:The transient period of regeneration potential in the postnatal heart suggests molecular changes with maturation influence the cardiac response to damage. We have previously demonstrated that injury and exercise can stimulate cardiomyocyte proliferation in the adult heart suggesting a sensitivity to exogenous signals. Here, we consider whether exogenous fetal ECM and mechanically unloading interstitial matrix can drive regeneration after myocardial infarction (MI) surgery in low-regenerative hearts of day5 mice. Compared to controls, exogenous fetal ECM increases cardiac function and lowers fibrosis at 3 weeks post-injury and this effect can be augmented by softening heart tissue. In vitro experiments support a mechano-sensitivity to exogenous ECM signaling. We tested potential mechanisms and observed that fetal ECM increases nuclear YAP localization which could be enhanced by pharmacological stabilization of the cytoskeleton. Blocking YAP expression lowered fetal ECM effects though not completely. Lastly we observed mechanically unloading heart interstitial matrix increased agrin expression, an extracellular node in the YAP signaling pathway. Collectively, these data support a combined effect of exogenous factors and mechanical activity in altering agrin expression, cytoskeletal remodeling, and YAP signaling in driving cardiomyocyte cell cycle activity and regeneration in postnatal non-regenerative mice. STATEMENT OF SIGNIFICANCE: With the purpose of developing regenerative strategies, we investigate the influence of the local niche on the cardiac injury response. We conclude tissue stiffness, as anticipated in aging or disease, impairs regenerative therapeutics. Most novel, mechanical unloading facilitates enhanced cardiac regeneration only after cells are pushed into a permissive state by fetal biomolecules. Specifically, mechanical unloading appears to increase extracellular agrin expression that amplifies fetal-stimulation of nuclear YAP signaling which correlates with observed increases of cell cycle activity in cardiomyocytes. The results further suggest the cytoskeleton is critical to this interaction between mechanical unloading and independently actived YAP signaling. Using animal models, tissue explants, and cells, this work indicates that local mechanical stimuli can augment proliferating-permissive cardiomyocytes in the natural cardiac niche.

Dataset Information

Murine spleen tissue regeneration from neonatal spleen capsule requires lymphotoxin priming of stromal cells.

Publications

Murine spleen tissue regeneration from neonatal spleen capsule requires lymphotoxin priming of stromal cells.

Similar Datasets

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