Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells
Abstract
Definitive erythropoiesis usually occurs in the bone marrow or fetal liver, where erythroblasts are associated with a central macrophage in anatomical units called 'blood islands'. Late in erythropoiesis, nuclei are expelled from the erythroid precursor cells and engulfed by the macrophages in the blood island. Here we show that the nuclei are engulfed by macrophages only after they are disconnected from reticulocytes, and that phosphatidylserine, which is often used as an 'eat me' signal for apoptotic cells, is also used for the engulfment of nuclei expelled from erythroblasts. We investigated the mechanism behind the enucleation and engulfment processes by isolating late-stage erythroblasts from the spleens of phlebotomized mice. When these erythroblasts were cultured, the nuclei protruded spontaneously from the erythroblasts. A weak physical force could disconnect the nuclei from the reticulocytes. The released nuclei contained an undetectable level of ATP, and quickly exposed phosphatidylserine on their surface. Fetal liver macrophages efficiently engulfed the nuclei; masking the phosphatidylserine on the nuclei with the dominant-negative form of milk-fat-globule EGF8 (MFG-E8) prevented this engulfment.
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Erythroblasts expel their nuclei during differentiation and these are taken up by EIM after phosphatidylserine exposure via Tim4 and MerTK.
“It is well characterized that erythroblasts expel their nuclei during differentiation and that these are taken up by EIM after phosphatidylserine exposure via Tim4 and MER proto-oncogene, tyrosine kinase (MerTK) [234, 254].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [254]
Cites
Flow-mediated endothelial mechanotransduction
Davies, P. F. (1995) · Physiological Reviews · doi:10.1152/physrev.1995.75.3.519 · Cited by 2,802 · see citing works
A receptor for phosphatidylserine-specific clearance of apoptotic cells
Fadok, V. A., Bratton, D. L., Rose, D. M., Pearson, A. M., Ezekowitz, R. A. B., & Henson, P. M. (2000) · Nature · doi:10.1038/35011084 · Cited by 1,491 · see citing works
Identification of a factor that links apoptotic cells to phagocytes
Hanayama, R., Tanaka, M., Miwa, K., Shinohara, A., Iwamatsu, A., & Nagata, S. (2002) · Nature · doi:10.1038/417182a · Cited by 1,401 · see citing works
Self-citationGreen, D. R., & Evan, G. I. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00024-7 · Cited by 1,254 · see citing works
Wu, H., Liu, X., Jaenisch, R., & Lodish, H. F. (1995) · Cell · doi:10.1016/0092-8674(95)90234-1 · Cited by 1,007 · see citing works
Autoimmune Disease and Impaired Uptake of Apoptotic Cells in MFG-E8-Deficient Mice
Hanayama, R., Tanaka, M., Miyasaka, K., Aozasa, K., Koike, M., Uchiyama, Y., & Nagata, S. (2004) · Science · doi:10.1126/science.1094359 · Cited by 992 · see citing works
Self-citationThe role of phosphatidylserine in recognition of apoptotic cells by phagocytes
Fadok, V. A., Bratton, D. L., Frasch, S. C., Warner, M. L., & Henson, P. M. (1998) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400404 · Cited by 776 · see citing works
Ineffective erythropoiesis in Stat5a−/−5b−/− mice due to decreased survival of early erythroblasts
Socolovsky, M., Nam, H.-S., Fleming, M. D., Haase, V. H., Brugnara, C., & Lodish, H. F. (2001) · Blood · doi:10.1182/blood.v98.12.3261 · Cited by 674 · see citing works
Takeshita, S., Kaji, K., & Kudō, A. (2000) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2000.15.8.1477 · Cited by 602 · see citing works
A Subfamily of P-Type ATPases with Aminophospholipid Transporting Activity
Tang, X., Halleck, M. S., Schlegel, R., & Williamson, P. (1996) · Science · doi:10.1126/science.272.5267.1495 · Cited by 471 · see citing works
Caspase Activation Is Required for Terminal Erythroid Differentiation
Zermati, Y., Garrido, C., Amsellem, S., Fishelson, S., Bouscary, D., Valensi, F., Varet, B. R., Solary, É., & Hermine, O. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.2.247 · Cited by 400 · see citing works
Aminophospholipid Asymmetry: A Matter of Life and Death
Balasubramanian, K., & Schroit, A. J. (2003) · Annual Review of Physiology · doi:10.1146/annurev.physiol.65.092101.142459 · Cited by 396 · see citing works
Molecular Cloning of Human Plasma Membrane Phospholipid Scramblase
Zhou, Q., Zhao, J., Stout, J. G., et al. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.29.18240 · Cited by 388 · see citing works
Requirement of DNase II for Definitive Erythropoiesis in the Mouse Fetal Liver
Kawane, K., Fukuyama, H., Kondoh, G., Takeda, J., Ohsawa, Y., Uchiyama, Y., & Nagata, S. (2001) · Science · doi:10.1126/science.292.5521.1546 · Cited by 387 · see citing works
Self-citationAsano, K., Miwa, M., Miwa, K., Hanayama, R., Nagase, H., Nagata, S., & Tanaka, M. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040342 · Cited by 268 · see citing works
Self-citationErythropoietin receptor characteristics on primary human erythroid cells
Broudy, V., Lin, N., Brice, M. C., Nakamoto, B., & Papayannopoulou, T. (1991) · Blood · doi:10.1182/blood.v77.12.2583.2583 · Cited by 255 · see citing works
Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation
Kawane, K., Fukuyama, H., Yoshida, H., Nagase, H., Ohsawa, Y., Uchiyama, Y., Okada, K., Iida, T., & Nagata, S. (2003) · Nature Immunology · doi:10.1038/ni881 · Cited by 228 · see citing works
Self-citationZhou, Q., Zhao, J., Wiedmer, T., & Sims, P. J. (2002) · Blood · doi:10.1182/blood-2001-12-0271 · Cited by 219 · see citing works
Krahling, S., Callahan, M. K., Williamson, P., & Schlegel, R. (1999) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400473 · Cited by 211 · see citing works
Caspase-3 has a nonapoptotic function in erythroid maturation
Carlile, G. W., Smith, D. H., & Wiedmann, M. (2004) · Blood · doi:10.1182/blood-2003-09-3362 · Cited by 183 · see citing works
Calcium Pumps of Plasma Membrane and Cell Interior
Strehler, E. E., & Treiman, M. (2004) · Current Molecular Medicine · doi:10.2174/1566524043360735 · Cited by 166 · see citing works
Hanayama, R., Tanaka, M., Miwa, K., & Nagata, S. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.6.3876 · Cited by 142 · see citing works
Self-citationBinding of merocyanine 540 to normal and leukemic erythroid cells
Schlegel, R. (1980) · Cell · doi:10.1016/0092-8674(80)90618-2 · Cited by 127 · see citing works
Molecular changes in the membranes of mouse erythroid cells accompanying differentiation
Geiduschek, J. B., & Singer, S. J. (1979) · Cell · doi:10.1016/0092-8674(79)90196-x · Cited by 119 · see citing works
Kawasaki, Y., Nakagawa, A., Nagaosa, K., Shiratsuchi, A., & Nakanishi, Y. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202879200 · Cited by 114 · see citing works
Role of the macrophage in erythropoiesis
Sadahira, Y., & Mori, M. (1999) · Pathology International · doi:10.1046/j.1440-1827.1999.00954.x · Cited by 77 · see citing works
Erythropoiesis: comparison of in vivo and in vitro amplification.
BESSIS, M. C., Mize, C. E., & Prenant, M. (1978) · PubMed · Cited by 58 · see citing works
Importance of cell-cell interactions in regulation of erythropoiesis
Hanspal, M. (1997) · Current Opinion in Hematology · doi:10.1097/00062752-199704020-00011 · Cited by 47 · see citing works
Hide and seek: the secret identity of the phosphatidylserine receptor.
Williamson, P., & Schlegel, R. (2004) · Journal of Biology · doi:10.1186/jbiol14 · Cited by 38 · see citing works
An optimized system for studies of EPO-dependent murine pro-erythroblast development
Zhang, D., Johnson, M. M., Miller, C. P., et al. (2001) · Experimental Hematology · doi:10.1016/s0301-472x(01)00725-1 · Cited by 20 · see citing works
Effect of Bleeding on in vivo and in vitro Colony-Forming Hemopoietic Cells
Pannacciulli, I. M., Massa, G. G., Saviane, A., et al. (2009) · Acta Haematologica · doi:10.1159/000207802 · Cited by 14 · see citing works
The effect of cytochalasin B on the enucleation of erythroid cells in vitro
Repasky, E. A., & Eckert, B. (1981) · Cell and Tissue Research · doi:10.1007/bf00216572 · Cited by 13 · see citing works
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Davies, L. C., Jenkins, S. J., Allen, J. E., & Taylor, P. R. (2013) · Nature Immunology · doi:10.1038/ni.2705 · Cited by 2,096 · see citing works
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Sandoval, H., Thiagarajan, P., Dasgupta, S. K., Schumacher, A., Prchal, J. T., Chen, M., & Wang, J. (2008) · Nature · doi:10.1038/nature07006 · Cited by 1,185 · see citing works
Identification of Tim4 as a phosphatidylserine receptor
Miyanishi, M., Tada, K., Koike, M., Uchiyama, Y., Kitamura, T., & Nagata, S. (2007) · Nature · doi:10.1038/nature06307 · Cited by 1,180 · see citing works
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Ramos, P., Casu, C., Gardenghi, S., Breda, L., Crielaard, B. J., Guy, E., Marongiu, M. F., Gupta, R., Levine, R. L., Abdel-Wahab, O., et al. (2013) · Nature Medicine · doi:10.1038/nm.3126 · Cited by 227 · see citing works
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- Authors
- Yoshida, H., Kawane, K., Koike, M., Mori, Y., Uchiyama, Y., & Nagata, S.
- Affiliations
- The University of Osaka (JP)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Nagata, Shigekazu
- Venue
- Nature
- Published
- 2005-09
- Volume
- 437
- Issue
- 7059
- Pages
- 754-758
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1999184263
- Cited by
- 346
- References
- 32
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 19 · 2023: 12 · 2022: 12 · 2021: 26 · 2020: 15 · 2019: 9 · 2018: 17 · 2017: 25 · 2016: 14 · 2015: 15 · 2014: 16 · 2013: 16 · 2012: 22
- FWCI
- 6.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Physiology › Erythrocyte Function and Pathophysiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- phosphatidylserine, macrophage engulfment, erythropoiesis, erythroblasts, blood islands, MFG-E8, phagocytosis, reticulocytes
- MeSH terms
- Adenosine Triphosphate, Animals, Antigens, Surface, Calcium, Cell Nucleus, Endocytosis, Erythroblasts, Erythropoiesis, Flow Cytometry, Macrophages, Mice, Inbred C57BL, Milk Proteins, Phosphatidylserines, Reticulocytes, Spleen, Erythroid Precursor Cells, Apoptosis, Phlebotomy, Mice
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