The tubules of the kidney display a remarkable capacity for self-renewal on damage. Whether this regeneration is mediated by dedifferentiating surviving cells or, as recently suggested, by stem cells has not been unequivocally settled. Herein, we demonstrate that aldehyde dehydrogenase (ALDH) activity may be used for isolation of cells with progenitor characteristics from adult human renal cortical tissue. Gene expression profiling of the isolated ALDH high and ALDH low cell fractions followed by immunohistochemical interrogation of renal tissues enabled us to delineate a tentative progenitor cell population scattered through the proximal tubules (PTs). These cells expressed CD24 and

Mast cells reside in tissues, where upon activation through the high-affinity-IgE-receptor (FcεRI) they degranulate and orchestrate the allergic reaction. Mast cells survive this activation and can thus be reactivated. In this study we demonstrate that this process depends on the pro-survival gene A1. Activation of mast cells through FcεRI resulted in degranulation, strong induction of A1 mRNA and protein, and cell survival. In contrast, A1-deficient mast cells released granule mediators similar to the wild-type control, but the cells did not survive an allergic activation. Furthermore, A1−/− mice that had been sensitized and provocated with allergen exhibited a lower number of mast cell compared with littermate controls. The induction of A1 was dependent on calcium, as EDTA prevented A1 expression. The calcium ionophore, ionomycin, induced A1 expression and mast cell survival, whereas compound 48/80, a well-known mast cell secretagogue, did not. This study uncovers the importance of A1 for mast cell survival in allergic reactions, and it proposes A1 as a potential target for the treatment of allergic diseases.

Mast cells are involved in many disorders where the triggering mechanism that leads to degranulation and/or cytokine secretion has not been defined. Several chronic inflammatory diseases are associated with increased mast cell numbers and upregulation of the TNF receptor family member CD30, but the role of elevated CD30 expression is poorly understood. Here we report what we believe to be a novel way to activate mast cells with CD30 that leads to degranulation-independent secretion of chemokines. CD30 induced a de novo synthesis and secretion of the chemokines IL-8, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β, a process involving the MAPK/ERK pathway. Mast cells were found to be the predominant CD30 ligand-positive (CD30L-positive) cell in the chronic inflammatory skin diseases psoriasis and atopic dermatitis, and both CD30 and CD30L expression were upregulated in lesional skin in these conditions. Furthermore, the number of IL-8-positive mast cells was elevated both in psoriatic and atopic dermatitis lesional skin as well as in ex vivo CD30-treated healthy skin organ cultures. In summary, characterization of CD30 activation of mast cells has uncovered an IgE-independent pathway that is of importance in understanding the entirety of the role of mast cells in diseases associated with mast cells and CD30 expression. These diseases include Hodgkin lymphoma, atopic dermatitis, and psoriasis.

Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl- 2 IntroductionMast cells are long-lived multifunctional effector cells of the immune system originating from the hematopoietic CD34 ϩ stem cells found in the bone marrow. 1 From the bone marrow, mast cell precursors enter the circulation where they are recruited into peripheral tissues to mature and express their final phenotype under the influence of stem cell factor (SCF) and other locally produced cytokines. 2 Although best known for their role in allergic reactions, mast cells are now also recognized as cells of importance in both innate immunity and in the onset and severity of chronic inflammations. 3,4 The versatile effector mechanisms mast cells have been endowed with can be deduced from their capability to release a wide variety of inflammatory mediators such as histamine, proteases, and cytokines that are preformed and stored in granules and prostaglandins, leukotrienes, and cytokines that are secreted upon activation. 5 The number of tissue mast cells is normally relatively constant, but during an acute or chronic inflammation the number can increase substantially. 6 The regulation of mast cell numbers is most likely regulated by proliferation, migration, and apoptosis or survival. The mechanisms that regulate the viability of mature mast cells or promote mast cell apoptosis are poorly investigated. SCF is a cardinal growth factor in mast cell biology, regulating mast cell growth, differentiation, adhesion, migration, and survival. 7 The number of tissue mast cells is at least in part regulated by SCF produced by resident stromal cells. SCF rescues mast cells from spontaneous apoptosis in vitro, whereas inhibition of SCF synthesis in vivo leads to mast cell apoptosis. [8][9][10] Although it is accepted that SCF is a prosurvival factor for mast cells, it remains largely unclear how SCF promotes survival in these cells.The B-cell lymphoma-2 (Bcl-2) family, which contains both prosurvival and proapoptotic proteins, are essential regulators of cell survival and apoptosis. 11 The levels and interactions of prosurvival versus proapoptotic Bcl-2 family proteins determine whether a cell survives or will undergo apoptosis. During apoptosis induced by proapoptotic Bcl-2 family members, cytochrome c is released from the mitochondria and a caspase cascade is activated that induces DNA fragmentation. 12,13 The prosurvival Bcl-2 family members include Bcl-2, Bcl-X L , Bcl-w, Mcl-1 (myeloid cell For personal use only. on May 12, 2018. by guest www.bloodjournal.org From leuk...