Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells

Yoshida, Hideyuki; Kawane, Kohki; Koike, Masato; Mori, Yasuhisa; Uchiyama, Yasuo; Nagata, Shinji

doi:10.1038/nature03964

Cited by 291 publications

(282 citation statements)

References 30 publications

(7 reference statements)

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“…PS is usually localized to the inner surface of plasma membranes; this localization is maintained by a putative ATP-dependent translocase (29). We recently found that the nuclei expelled from erythroid precursor cells are deprived of ATP and expose PS on their surface (24). Similarly, MFGs carry few organelles such as mitochondria; therefore, ATP would be depleted in MFGs, thus inactivating the translocase and leading to the exposure of PS on the outer surface of MFG-E8 ϩ/Ϫ or MFG-E8 Ϫ/Ϫ dams were allowed to lactate pups for 5 days and then forced to wean.…”

Section: Discussionmentioning

confidence: 99%

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Hanayama

Nagata

2005

Proc. Natl. Acad. Sci. U.S.A.

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120

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During the involution of mammary glands, epithelial cells undergo apoptosis and are cleared for the next cycle of lactation. The clearance of apoptotic epithelial cells is mediated by neighboring epithelial cells and by macrophages that migrate into the mammary glands. Here, we report that milk fat globule EGF factor 8 (MFG-E8), a secreted glycoprotein that binds to apoptotic cells by recognizing phosphatidylserine, was expressed by epithelial cells and macrophages in mammary glands and was involved in engulfment of apoptotic cells. A deficiency of MFG-E8 caused the accumulation of a large number of milk fat globules (MFGs) in the mammary ducts during involution, indicating that the excess MFGs were cleared by an MFG-E8-dependent mechanism. The MFG-E8 ؊/؊ mice developed mammary duct ectasia with periductal mastitis, and the redevelopment of the mammary gland for their second litter was impaired. These results demonstrate that MFG-E8-mediated phagocytosis of apoptotic epithelial cells and MFGs is important for efficient involution of mammary glands.exosomes ͉ mastitis ͉ phosphatidylserine M ammary glands are unique mammalian organs that are developed to nurse offspring. For each pregnancy, the glands undergo a cycle of development, lactation, and involution. In each cycle, mammalian epithelial cells proliferate, differentiate, and die. The involution of mammary glands is triggered when the suckling stimulus is lost, usually upon weaning, and milk accumulates in the glands. The involution takes Ϸ10 days in mice and can be divided into two phases (1-3). In the first phase, which is reversible and lasts 48 h after weaning, mammary epithelial cells lose their differentiated function. In the second phase, the basement membranes and extracellular matrix in the mammary glands are degraded by proteases, leading to destruction of the lobular-alveolar architecture of the mammary glands. As involution progresses, mammary epithelial cells are removed and adipocytes concomitantly reappear, and the lobular-alveolar structure is reorganized to approach that of virgin glands (4).During the involution process, epithelial cells undergo apoptosis and are shed into the lumen (5). At the initial stage of involution, these apoptotic cells are thought to be engulfed mainly by neighboring epithelial cells; in the later stage, they seem to be cleared by macrophages that migrate into the gland (3, 6). Milk fat globules (MFGs) are minute globules carrying fat that are secreted from the epithelial cells into the lumen during lactation (7). Upon weaning, many MFGs remain in the lumen, and they seem to be engulfed by epithelial cells lining the lobules in the mammary gland (8). How these epithelial cells and macrophages recognize and engulf apoptotic cells and MFGs has not been well elucidated.Many molecules expressed on the surface of apoptotic cells or phagocytes have been proposed as ligands and receptors for the engulfment of apoptotic cells (9 -11). Mouse MFG EGF factor 8 (MFG-E8), called lactadherin in humans, is a 72-kDa glycoprotein s...

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Section: Discussionmentioning

confidence: 99%

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Hanayama

Nagata

2005

Proc. Natl. Acad. Sci. U.S.A.

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120

118

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“…Besides apoptotic cells, the exposure of PS on pyrenocytes (that is, the erythroid nucleus extruded from the erythroblast during the final stage of erythrocyte differentiation) can also facilitate their removal by macrophages. 19,20 Furthermore, it is important to note that the phospholipid code on dying cells can undergo further changes when the plasma membrane is permeabilized to generate necrotic cells. 4 This is particularly evident when healthy cells are exposed to extreme chemical or physical assault to generate primary necrotic cells, or when apoptotic cells are not promptly removed and resulted in the formation of late apoptotic cells (also known as secondary necrotic cells).…”

Section: Box 1 Phospholipids As Key Regulators Of Intracellular Procementioning

confidence: 99%

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

2015

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A significant effort is made by the cell to maintain certain phospholipids at specific sites. It is well described that proteins involved in intracellular signaling can be targeted to the plasma membrane and organelles through phospholipid-binding domains. Thus, the accumulation of a specific combination of phospholipids, denoted here as the 'phospholipid code', is key in initiating cellular processes. Interestingly, a variety of extracellular proteins and pathogen-derived proteins can also recognize or modify phospholipids to facilitate the recognition of dying cells, tumorigenesis and host-microbe interactions. In this article, we discuss the importance of the phospholipid code in a range of physiological and pathological processes.

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“…[1][2][3] Proposed roles for macrophages in erythroid differentiation include a simple scaffolding function, 4 promotion of red cell proliferation, 5 provision of concentrated EPO, direct transfer of iron or iron-regulating factors, 6 inhibition of apoptosis, and more recently clear evidence has emerged testifying to the importance of macrophages in the engulfment of nuclei extruded by mature red cells. 7 Mice carrying a targeted deletion of the Rb tumor suppressor gene in their germ line die at E13.5 to E14.5 of gestation, exhibiting extensive cell death in multiple tissues, including the fetal liver, and this has been attributed to systemic ischemia due to defective placental function and anemia. 8,9 The production of enucleated mature red blood cells appeared normal in mice derived from germ-line Rb-null chimeras 10 and in conditionally targeted E15.5 embryos in which Rb was not deleted in the placenta.…”

Section: Introductionmentioning

confidence: 99%

Hypoxic stress underlies defects in erythroblast islands in the Rb-null mouse

Dibling¹,

Macleod

2007

Blood

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Definitive erythropoiesis occurs in islands composed of a central macrophage in contact with differentiating erythroblasts. Erythroid maturation including enucleation can also occur in the absence of macrophages both in vivo and in vitro. We reported previously that loss of Rb induces cell-autonomous defects in red cell maturation under stress conditions, while other reports have suggested that the failure of Rb-null erythroblasts to enucleate is due to defects in associated macrophages. Here we show that erythropoietic islands are disrupted by hypoxic stress, such as occurs in the Rb-null fetal liver, that Rb ؊/؊ macrophages are competent for erythropoietic island formation in the absence of exogenous stress and that enucleation defects persist in Rb-null erythroblasts irrespective of macrophage function.

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Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells

Cited by 291 publications

References 30 publications

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

Hypoxic stress underlies defects in erythroblast islands in the Rb-null mouse

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