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Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis.

ABSTRACT: The immune system develops in waves during ontogeny; it is initially populated by cells generated from fetal hematopoietic stem cells (HSCs) and later by cells derived from adult HSCs. Remarkably, the genetic programs that control these two distinct stem cell fates remain poorly understood. We report that Lin28b is specifically expressed in mouse and human fetal liver and thymus, but not in adult bone marrow or thymus. We demonstrate that ectopic expression of Lin28 reprograms hematopoietic stem/progenitor cells (HSPCs) from adult bone marrow, which endows them with the ability to mediate multilineage reconstitution that resembles fetal lymphopoiesis, including increased development of B-1a, marginal zone B, gamma/delta (??) T cells, and natural killer T (NKT) cells.

SUBMITTER: Yuan J

PROVIDER: S-EPMC3471381 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis.

Yuan Joan J Nguyen Cuong K CK Liu Xiuhuai X Kanellopoulou Chrysi C Muljo Stefan A SA

Science (New York, N.Y.) 20120216 6073

The immune system develops in waves during ontogeny; it is initially populated by cells generated from fetal hematopoietic stem cells (HSCs) and later by cells derived from adult HSCs. Remarkably, the genetic programs that control these two distinct stem cell fates remain poorly understood. We report that Lin28b is specifically expressed in mouse and human fetal liver and thymus, but not in adult bone marrow or thymus. We demonstrate that ectopic expression of Lin28 reprograms hematopoietic stem ...[more]

PMID: 22345399

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Lin28b expression distinguishes fetal versus adult lymphopoiesis

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Lin28b expression distinguishes fetal versus adult lymphopoiesis

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Rap1 signal modulators control the maintenance of hematopoietic progenitors in bone marrow and adult long-term hematopoiesis.

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Distinct changes in adult lymphopoiesis in Rag2-/- mice fully reconstituted by alpha4-deficient adult bone marrow cells.

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Developmental switch of mouse hematopoietic stem cells from fetal to adult type occurs in bone marrow after birth.

Project description:Hematopoiesis originated by hematopoietic stem cells (HSCs) is distinguishable between fetal and adult mice. However, it is not clear whether the altered mode of differentiation is due to the change of properties of HSCs or different microenvironments in fetuses and adults. Here we show that fetal HSCs are fully capable of giving rise to all classes of B cells in the adult microenvironment. HSCs that are derived from fetal liver but not adult bone marrow (BM) of IL-7 receptor alpha chain (IL-7Ralpha)-deficient mice can also differentiate into B cells, suggesting that both IL-7 and thymic stromal-derived lymphopoietin (TSLP) are dispensable for fetal B cell development, because IL-7Ralpha is commonly used as a subunit of functional receptor complexes for IL-7 and TSLP. Similar IL-7/TSLP independent B cell potential is maintained by BM HSCs until 1 week after birth. In contrast, BM HSCs in mice older than 2 weeks of age absolutely requires IL-7Ralpha for B lymphopoiesis. These results demonstrate that fetal HSCs acquired adult characteristics between 1 and 2 weeks after birth in mouse BM.

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Glucocorticoids Regulate Bone Marrow B Lymphopoiesis After Stroke.

Project description:RationaleAfter a stroke, patients frequently experience altered systemic immunity resulting in peripheral immunosuppression and higher susceptibility to infections, which is at least partly attributed to lymphopenia. The mechanisms that profoundly change the systemic leukocyte repertoire after stroke are incompletely understood. Emerging evidence indicates that stroke alters hematopoietic output of the bone marrow.ObjectiveTo explore the mechanisms that lead to defects of B lymphopoiesis after ischemic stroke.Methods and resultsWe here report that ischemic stroke triggers brain-bone marrow communication via hormonal long-range signals that regulate hematopoietic B lineage decisions. Bone marrow fluorescence-activated cell sorter analyses and serial intravital microscopy indicate that transient middle cerebral artery occlusion in mice arrests B-cell development beginning at the pro-B-cell stage. This phenotype was not rescued in Myd88-/- and TLR4-/- mice with disrupted TLR (Toll-like receptor) signaling or after blockage of peripheral sympathetic nerves. Mechanistically, we identified stroke-induced glucocorticoid release as the main instigator of B lymphopoiesis defects. B-cell lineage-specific deletion of the GR (glucocorticoid receptor) in CD19-Cre loxP Nr3c1 mice attenuated lymphocytopenia after transient middle cerebral artery. In 20 patients with acute stroke, increased cortisol levels inversely correlated with blood lymphocyte numbers.ConclusionsOur data demonstrate that the hypothalamic-pituitary-adrenal axis mediates B lymphopoiesis defects after ischemic stroke.

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Cell cycle quiescence of early lymphoid progenitors in adult bone marrow.

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