Encarnacion Montecino-Rodriguez

Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene

Prolactin (PRL) has been implicated in numerous physiological and developmental processes. The mouse PRL gene was disrupted by homologous recombination. The mutation caused infertility in female mice, but did not prevent female mice from manifesting spontaneous maternal behaviors. PRL‐deficient males were fertile and produced offspring with normal Mendelian gender and genotype ratios when they were mated with heterozygous females. Mammary glands of mutant female mice developed a normal ductal tree, but the ducts failed to develop lobular decorations, which is a characteristic of the normal virgin adult mammary gland. The potential effect of PRL gene disruption on antigen‐independent primary hematopoiesis was assessed. The results of this analysis indicated that myelopoiesis and primary lymphopoiesis were unaltered in the mutant mice. Consistent with these observations in PRL mutant mice, PRL failed to correct the bone marrow B cell deficiency of Snell dwarf mice. These results argue that PRL does not play any indispensable role in primary lymphocyte development and homeostasis, or in myeloid differentiation. The PRL−/− mouse model provides a new research tool with which to resolve a variety of questions regarding the involvement of both endocrine and paracrine sources of PRL in reproduction, lactogenesis, tumorigenesis and immunoregulation.

The ageing immune system: is it ever too old to become young again?

Ageing is accompanied by a decline in the function of the immune system, which increases susceptibility to infections and can decrease the quality of life. The ability to rejuvenate the ageing immune system would therefore be beneficial for elderly individuals and would decrease health-care costs for society. But is the immune system ever too old to become young again? We review here the promise of various approaches to rejuvenate the function of the immune system in the rapidly growing ageing population.

Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-β

Duchenne muscular dystrophy (DMD) is an X-linked, degenerative muscle disease that is exacerbated by secondary inflammation. Here, we characterized the immunological milieu of dystrophic muscle in mdx mice, a model of DMD, to identify potential therapeutic targets. We identified a specific subpopulation of cells expressing the Vbeta8.1/8.2 TCR that is predominant among TCR-beta+ T cells. These cells expressed high levels of osteopontin (OPN), a cytokine that promotes immune cell migration and survival. Elevated OPN levels correlated with the dystrophic process, since OPN was substantially elevated in the serum of mdx mice and muscle biopsies after disease onset. Muscle biopsies from individuals with DMD also had elevated OPN levels. To test the role of OPN in mdx muscle, mice lacking both OPN and dystrophin were generated and termed double-mutant mice (DMM mice). Reduced infiltration of NKT-like cells and neutrophils was observed in the muscle of DMM mice, supporting an immunomodulatory role for OPN in mdx muscle. Concomitantly, an increase in CD4+ and FoxP3+ Tregs was also observed in DMM muscle, which also showed reduced levels of TGF-beta, a known fibrosis mediator. These inflammatory changes correlated with increased strength and reduced diaphragm and cardiac fibrosis. These studies suggest that OPN may be a promising therapeutic target for reducing inflammation and fibrosis in individuals with DMD.

Bipotential B-macrophage progenitors are present in adult bone marrow

According to the current model of adult hematopoiesis, differentiation of pluripotential hematopoietic stem cells into common myeloid- and lymphoid-committed progenitors establishes an early separation between the myeloid and lymphoid lineages. This report describes a rare and previously unidentified CD45R−CD19+ B cell progenitor population in postnatal bone marrow that can also generate macrophages. In addition to the definition of this B-lineage intermediate, the data indicate that a developmental relationship between the B and macrophage lineages is retained during postnatal hematopoiesis.

Reduction in the Developmental Potential of Intrathymic T Cell Progenitors with Age

Current models of thymic involution propose that intrinsic developmental defects in intrathymic T cell precursors do not contribute to age-related declines in thymopoiesis. This premise was reassessed in a murine model in light of the recent definition of the early T lineage progenitor (ETP), which appears to be the earliest intrathymic precursor defined to date. The results demonstrate that the frequency of ETP declines with age and their potential to reconstitute the thymus is diminished. These findings are consistent with the fact that ETP from aged mice proliferate less and have a higher rate of apoptosis than their counterparts from young animals. Taken together, these data suggest that age-associated changes in T cell precursors should be considered when attempts to rejuvenate the involuted thymus are made.

B-1 B Cell Development in the Fetus and Adult

Models of hematopoiesis often depict lymphocyte production as a uniform process in which a homogenous population of hematopoietic stem cells (HSCs) generates progenitors from which all types of lymphocytes are derived. However, it is increasingly evident that these schemes are too simplistic and that the lymphoid potential of HSCs and precursors arising in the embryo, fetus, neonate, and adult is remarkably distinct. We review recent findings regarding the development of B lymphocytes, and the B-1 B cell lineage in particular, as a case in point. These studies show that B-1 and B-2 B cells involved in innate and adaptive immune responses, respectively, arise in staggered waves of development from distinct progenitors. We discuss the implications of this layered model of B cell development for understanding normal and dysregulated B lymphopoiesis.

Causes, consequences, and reversal of immune system aging

The effects of aging on the immune system are manifest at multiple levels that include reduced production of B and T cells in bone marrow and thymus and diminished function of mature lymphocytes in secondary lymphoid tissues. As a result, elderly individuals do not respond to immune challenge as robustly as the young. An important goal of aging research is to define the cellular changes that occur in the immune system and the molecular events that underlie them. Considerable progress has been made in this regard, and this information has provided the rationale for clinical trials to rejuvenate the aging immune system.

Embryonic day 9 yolk sac and intra-embryonic hemogenic endothelium independently generate a B-1 and marginal zone progenitor lacking B-2 potential

The majority of B lymphocytes in the adult mouse are generated in the bone marrow from hematopoietic stem cells (HSCs) that first appear in the aorta-gonado-mesonephros region of the fetus on embryonic day (E) 10.5–11. Comparatively less is known about B-cell development during embryogenesis. For example, which specific embryonic tissues participate in B lymphopoiesis and whether hematopoietic differentiation is skewed toward specific B-cell subsets in the embryo are unanswered questions, because the systemic circulation is initiated early during embryogenesis, resulting in an admixture of cells potentially originating from multiple sites. We demonstrate, using Ncx1−/− mice that lack systemic blood circulation, that the E9 yolk sac (YS) and the intra-embryonic para-aortic splanchnopleura (P-Sp) tissues independently give rise to AA4.1+CD19+B220lo-neg B progenitor cells that preferentially differentiate into innate type B-1 and marginal zone (MZ) B cells but not into B-2 cells upon transplantation. We have further demonstrated that these B-1 progenitor cells arise directly from YS and P-Sp hemogenic endothelium. These results document the initial wave of innate B lymphopoietic progenitor cells available for seeding the fetal liver at E11. The results of these studies expand our knowledge of hemogenic endothelial sites specifying distinct B-1 and MZ cell fates apart from B-2 cells and independent of an HSC origin during development.

Fetal B-cell lymphopoiesis and the emergence of B-1-cell potential

Most B cells in peripheral lymphoid tissues are produced in adult bone marrow and are referred to as B-2 cells. A minor B-cell population, known as the B-1-cell population, that is mainly involved in innate immune responses has been identified in mice. In contrast to B-2 cells, B-1-cell progenitors are produced most efficiently during fetal life. This Review focuses on the emergence of B-1-cell potential during embryogenesis, summarizes recent advances in the delineation of a fetal B-1-cell-specified progenitor, and discusses the possibility that distinct fetal and adult B-cell developmental programmes might be operative in humans.

Effects of Aging on the Common Lymphoid Progenitor to Pro-B Cell Transition

The number of common lymphoid progenitors (CLP) and their pre-pro-B and pro-B cell progeny is reduced in old mice, but the age-related changes responsible for these declines have not been fully elucidated. The aim of this study was to provide additional insights into the impact of senescence on early B cell development by analyzing the CLP and pro-B cell compartments under steady-state conditions and after cytoablation with 5-fluorouracil. 5-Fluorouracil subjects the hemopoietic system to acute stress and has the advantage of revealing defects in progenitors that may otherwise be subtle. The data demonstrate significant, age-related defects in the proliferative potential of early B cell precursors and suggest that the ability of CLP to differentiate into pre-pro-B cells is also compromised by senescence. These age-related changes in early B lymphopoiesis do not result from a general defect in HSC or the bone marrow microenvironment that impairs development in all hemopoietic lineages. Instead, data demonstrating that myeloid progenitor number and developmental potential do not decline with age indicate that B lymphopoiesis is particularly sensitive to defects that accumulate during senescence.