Science China Life Sciences

, Volume 61, Issue 8, pp 885–892 | Cite as

Fetal liver: an ideal niche for hematopoietic stem cell expansion

  • Suwei Gao
  • Feng LiuEmail author


Fetal liver (FL) is an intricate and highly vascularized hematopoietic organ, which can support the extensive expansion of hematopoietic stem cells (HSCs) without loss of stemness, as well as of the downstream lineages of HSCs. This powerful function of FL largely benefits from the niche (or microenvironment), which provides a residence for HSC expansion. Numerous studies have demonstrated that the FL niche consists of heterogeneous cell populations that associate with HSCs spatially and regulate HSCs functionally. At the molecular level, a complex of cell extrinsic and intrinsic signaling network within the FL niche cells maintains HSC expansion. Here, we summarize recent studies on the analysis of the FL HSCs and their niche, and specifically on the molecular regulatory network for HSC expansion. Based on these studies, we hypothesize a strategy to obtain a large number of functional HSCs via 3D reconstruction of FL organoid ex vivo for clinical treatment in the future.


fetal liver niche hematopoietic stem cell expansion signaling network 


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We thank lab members for helpful discussions and critical reading of the paper. This work was supported by the National Natural Science Foundation of China (81530004, 31425016), the Ministry of Science and Technology of China (2016YFA0100500) and the Strategic Priority Research Program of the Chinese Academy of Sciences, China (XDA16010104).


  1. Acar, M., Kocherlakota, K.S., Murphy, M.M., Peyer, J.G., Oguro, H., Inra, C.N., Jaiyeola, C., Zhao, Z., Luby-Phelps, K., and Morrison, S.J. (2015). Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 526, 126–130CrossRefPubMedPubMedCentralGoogle Scholar
  2. Arora, N., Wenzel, P.L., McKinney-Freeman, S.L., Ross, S.J., Kim, P.G., Chou, S.S., Yoshimoto, M., Yoder, M.C., and Daley, G.Q. (2014). Effect of developmental stage of HSC and recipient on transplant outcomes. Dev Cell 29, 621–628CrossRefPubMedPubMedCentralGoogle Scholar
  3. Badylak, S.F. (2002). The extracellular matrix as a scaffold for tissue reconstruction. Semin Cell Dev Biol 13, 377–383CrossRefPubMedGoogle Scholar
  4. Baptista, P.M., Siddiqui, M.M., Lozier, G., Rodriguez, S.R., Atala, A., and Soker, S. (2011). The use of whole organ decellularization for the generation of a vascularized liver organoid. Hepatology 53, 604–617CrossRefPubMedGoogle Scholar
  5. Baumann, C.I., Bailey, A.S., Li, W., Ferkowicz, M.J., Yoder, M.C., and Fleming, W.H. (2004). PECAM-1 is expressed on hematopoietic stem cells throughout ontogeny and identifies a population of erythroid progenitors. Blood 104, 1010–1016CrossRefPubMedGoogle Scholar
  6. Bertrand, J.Y., Chi, N.C., Santoso, B., Teng, S., Stainier, D.Y.R., and Traver, D. (2010). Haematopoietic stem cells derive directly from aortic endothelium during development. Nature 464, 108–111CrossRefPubMedPubMedCentralGoogle Scholar
  7. Boisset, J.C., van Cappellen, W., Andrieu-Soler, C., Galjart, N., Dzierzak, E., and Robin, C. (2010). In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 464, 116–120CrossRefPubMedGoogle Scholar
  8. Boulais, P.E., and Frenette, P.S. (2015). Making sense of hematopoietic stem cell niches. Blood 125, 2621–2629CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chen, J., Suo, S., Tam, P.P., Han, J.D.J., Peng, G., and Jing, N. (2017). Spatial transcriptomic analysis of cryosectioned tissue samples with Geo-seq. Nat Protoc 12, 566–580CrossRefPubMedGoogle Scholar
  10. Chen, Y., Haviernik, P., Bunting, K.D., and Yang, Y.C. (2007). Cited2 is required for normal hematopoiesis in the murine fetal liver. Blood 110, 2889–2898CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chou, S., and Lodish, H.F. (2010). Fetal liver hepatic progenitors are supportive stromal cells for hematopoietic stem cells. Proc Natl Acad Sci USA 107, 7799–7804CrossRefPubMedGoogle Scholar
  12. Coskun, S., and Hirschi, K.K. (2010). Establishment and regulation of the HSC niche: roles of osteoblastic and vascular compartments. Birth Defects Res Part C Embryo Today Rev 90, 229–242CrossRefGoogle Scholar
  13. Crane, G.M., Jeffery, E., and Morrison, S.J. (2017). Adult haematopoietic stem cell niches. Nat Rev Immunol 17, 573–590.CrossRefPubMedGoogle Scholar
  14. de Bruijn, M.F.T.R., Speck, N.A., Peeters, M.C.E., and Dzierzak, E. (2000). Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. EMBO J 19, 2465–2474CrossRefPubMedPubMedCentralGoogle Scholar
  15. Ding, L., Saunders, T.L., Enikolopov, G., and Morrison, S.J. (2012). Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462CrossRefPubMedPubMedCentralGoogle Scholar
  16. Dzierzak, E., and Robin, C. (2010). Placenta as a source of hematopoietic stem cells. Trends Mol Med 16, 361–367CrossRefPubMedPubMedCentralGoogle Scholar
  17. Edling, C.E., and Hallberg, B. (2007). c-Kit—A hematopoietic cell essential receptor tyrosine kinase. Int J Biochem Cell Biol 39, 1995–1998CrossRefPubMedGoogle Scholar
  18. Ema, H., and Nakauchi, H. (2000). Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood 95, 2284–2288PubMedGoogle Scholar
  19. Felfly, H., and Haddad, G.G. (2014). Hematopoietic stem cells: potential new applications for translational medicine. J Stem Cells 9, 163–197PubMedGoogle Scholar
  20. Flanagan, J.G., and Leder, P. (1990). The kit ligand: A cell surface molecule altered in steel mutant fibroblasts. Cell 63, 185–194CrossRefPubMedGoogle Scholar
  21. Gao, X., Xu, C., Asada, N., and Frenette, P.S. (2018). The hematopoietic stem cell niche: from embryo to adult. Development 145, dev139691CrossRefPubMedGoogle Scholar
  22. Gekas, C., Dieterlen-Lièvre, F., Orkin, S.H., and Mikkola, H.K.A. (2005). The placenta is a niche for hematopoietic stem cells. Dev Cell 8, 365–375CrossRefPubMedGoogle Scholar
  23. Gerhardt, D.M., Pajcini, K.V., D’altri, T., Tu, L., Jain, R., Xu, L., Chen, M. J., Rentschler, S., Shestova, O., Wertheim, G.B., et al. (2014). The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells. Genes Dev 28, 576–593CrossRefPubMedPubMedCentralGoogle Scholar
  24. Grün, D., Kester, L., and van Oudenaarden, A. (2014). Validation of noise models for single-cell transcriptomics. Nat Methods 11, 637–640CrossRefPubMedGoogle Scholar
  25. Grün, D., and van Oudenaarden, A. (2015). Design and analysis of singlecell sequencing experiments. Cell 163, 799–810CrossRefPubMedGoogle Scholar
  26. Hackney, J.A., Charbord, P., Brunk, B.P., Stoeckert, C.J., Lemischka, I.R., and Moore, K.A. (2002). A molecular profile of a hematopoietic stem cell niche. Proc Natl Acad Sci USA 99, 13061–13066CrossRefPubMedGoogle Scholar
  27. Han, X., Wang, R., Zhou, Y., Fei, L., Sun, H., Lai, S., Saadatpour, A., Zhou, Z., Chen, H., Ye, F., et al. (2018). Mapping the mouse cell atlas by microwell-Seq. Cell 172, 1091–1107.e17CrossRefPubMedGoogle Scholar
  28. Harrison, D.E., Zhong, R.K., Jordan, C.T., Lemischka, I.R., and Astle, C. M. (1997). Relative to adult marrow, fetal liver repopulates nearly five times more effectively long-term than short-term. Exp Hematol 25, 293–297PubMedGoogle Scholar
  29. He, Q., Gao, S., Lv, J., Li, W., and Liu, F. (2017). BLOS2 maintains hematopoietic stem cells in the fetal liver via repressing Notch signaling. Exp Hematol 51, 1–6.e2CrossRefPubMedGoogle Scholar
  30. Hoeffel, G., Chen, J., Lavin, Y., Low, D., Almeida, F.F., See, P., Beaudin, A.E., Lum, J., Low, I., Forsberg, E.C., et al. (2015). C-Myb+ erythromyeloid progenitor-derived fetal monocytes give rise to adult tissueresident macrophages. Immunity 42, 665–678CrossRefPubMedPubMedCentralGoogle Scholar
  31. Hsu, H.C., Ema, H., Osawa, M., Nakamura, Y., Suda, T., and Nakauchi, H. (2000). Hematopoietic stem cells express Tie-2 receptor in the murine fetal liver. Blood 96, 3757–3762PubMedGoogle Scholar
  32. Ikuta, K., Kina, T., MacNeil, I., Uchida, N., Peault, B., Chien, Y., and Weissman, I.L. (1990). A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62, 863–874CrossRefPubMedGoogle Scholar
  33. Ikuta, K., and Weissman, I.L. (1992). Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation.. Proc Natl Acad Sci USA 89, 1502–1506CrossRefPubMedGoogle Scholar
  34. Iwasaki, H., Arai, F., Kubota, Y., Dahl, M., and Suda, T. (2010). Endothelial protein C receptor-expressing hematopoietic stem cells reside in the perisinusoidal niche in fetal liver. Blood 116, 544–553CrossRefPubMedGoogle Scholar
  35. Jassinskaja, M., Johansson, E., Kristiansen, T.A., Åkerstrand, H., Sjöholm, K., Hauri, S., Malmström, J., Yuan, J., and Hansson, J. (2017). Comprehensive proteomic characterization of ontogenic changes in hematopoietic stem and progenitor cells. Cell Rep 21, 3285–3297CrossRefPubMedGoogle Scholar
  36. Jordan, C.T., McKearn, J.P., and Lemischka, I.R. (1990). Cellular and developmental properties of fetal hematopoietic stem cells. Cell 61, 953–963CrossRefPubMedGoogle Scholar
  37. Khan, J.A., Mendelson, A., Kunisaki, Y., Birbrair, A., Kou, Y., Arnal-Estapé, A., Pinho, S., Ciero, P., Nakahara, F., Ma’ayan, A., et al. (2016). Fetal liver hematopoietic stem cell niches associate with portal vessels. Science 351, 176–180CrossRefPubMedGoogle Scholar
  38. Kieusseian, A., Brunet de la Grange, P., Burlen-Defranoux, O., Godin, I., and Cumano, A. (2012). Immature hematopoietic stem cells undergo maturation in the fetal liver. Development 139, 3521–3530CrossRefPubMedGoogle Scholar
  39. Kim, I., He, S., Yilmaz, O.H., Kiel, M.J., and Morrison, S.J. (2006). Enhanced purification of fetal liver hematopoietic stem cells using SLAM family receptors. Blood 108, 737–744CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kim, I., Yilmaz, O.H., and Morrison, S.J. (2005). CD144 (VE-cadherin) is transiently expressed by fetal liver hematopoietic stem cells. Blood 106, 903–905CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kissa, K., and Herbomel, P. (2010). Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 464, 112–115CrossRefPubMedGoogle Scholar
  42. Krosl, J., Mamo, A., Chagraoui, J., Wilhelm, B.T., Girard, S., Louis, I., Lessard, J., Perreault, C., and Sauvageau, G. (2010). A mutant allele of the Swi/Snf member BAF250a determines the pool size of fetal liver hemopoietic stem cell populations. Blood 116, 1678–1684CrossRefPubMedPubMedCentralGoogle Scholar
  43. Kubanek, B., Rencricca, N., Porcellini, A., Howard, D., and Stohlman, F. (1969). The pattern of recovery of erythropoiesis in heavily irradiated mice receiving transplants of fetal liver. Exp Biol Med 131, 831–834CrossRefGoogle Scholar
  44. Kunisaki, Y., Bruns, I., Scheiermann, C., Ahmed, J., Pinho, S., Zhang, D., Mizoguchi, T., Wei, Q., Lucas, D., Ito, K., et al. (2013). Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502, 637–643CrossRefPubMedPubMedCentralGoogle Scholar
  45. Li, C.L., and Johnson, G.R. (1994). Stem cell factor enhances the survival but not the self-renewal of murine hematopoietic long-term repopulating cells. Blood 84, 408–414PubMedGoogle Scholar
  46. Li, T., Huang, J., Jiang, Y., Zeng, Y., He, F., Zhang, M.Q., Han, Z., and Zhang, X. (2009). Multi-stage analysis of gene expression and transcription regulation in C57/B6 mouse liver development. Genomics 93, 235–242CrossRefPubMedGoogle Scholar
  47. Li, Z., Lan, Y., He, W., Chen, D., Wang, J., Zhou, F., Wang, Y., Sun, H., Chen, X., Xu, C., et al. (2012). Mouse embryonic head as a site for hematopoietic stem cell development. Cell Stem Cell 11, 663–675CrossRefPubMedGoogle Scholar
  48. Lin, M.I., Price, E.N., Boatman, S., Hagedorn, E.J., Trompouki, E., Satishchandran, S., Carspecken, C.W., Uong, A., DiBiase, A., Yang, S., et al. (2015). Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling. eLife 4, e05544CrossRefPubMedCentralGoogle Scholar
  49. Macosko, E.Z., Basu, A., Satija, R., Nemesh, J., Shekhar, K., Goldman, M., Tirosh, I., Bialas, A.R., Kamitaki, N., Martersteck, E.M., et al. (2015). Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202–1214CrossRefPubMedPubMedCentralGoogle Scholar
  50. Manesia, J.K., Xu, Z., Broekaert, D., Boon, R., van Vliet, A., Eelen, G., Vanwelden, T., Stegen, S., Van Gastel, N., Pascual-Montano, A., et al. (2015). Highly proliferative primitive fetal liver hematopoietic stem cells are fueled by oxidative metabolic pathways. Stem Cell Res 15, 715–721CrossRefPubMedGoogle Scholar
  51. McKinney-Freeman, S., Cahan, P., Li, H., Lacadie, S.A., Huang, H.T., Curran, M., Loewer, S., Naveiras, O., Kathrein, K.L., Konantz, M., et al. (2012). The transcriptional landscape of hematopoietic stem cell ontogeny. Cell Stem Cell 11, 701–714CrossRefPubMedPubMedCentralGoogle Scholar
  52. Medvinsky, A., and Dzierzak, E. (1996). Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86, 897–906CrossRefPubMedGoogle Scholar
  53. Metcalf, D. (2008). Hematopoietic cytokines. Blood 111, 485–491CrossRefPubMedPubMedCentralGoogle Scholar
  54. Mikkola, H.K.A., and Orkin, S.H. (2006). The journey of developing hematopoietic stem cells. Development 133, 3733–3744CrossRefPubMedGoogle Scholar
  55. Mochizuki-Kashio, M., Mishima, Y., Miyagi, S., Negishi, M., Saraya, A., Konuma, T., Shinga, J., Koseki, H., and Iwama, A. (2011). Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood 118, 6553–6561CrossRefPubMedGoogle Scholar
  56. Morrison, S.J., Hemmati, H.D., Wandycz, A.M., and Weissman, I.L. (1995). The purification and characterization of fetal liver hematopoietic stem cells. Proc Natl Acad Sci USA 92, 10302–10306CrossRefPubMedGoogle Scholar
  57. Morrison, S.J., and Scadden, D.T. (2014). The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334CrossRefPubMedPubMedCentralGoogle Scholar
  58. Munugalavadla, V., Dore, L.C., Tan, B.L., Hong, L., Vishnu, M., Weiss, M. J., and Kapur, R. (2005). Repression of c-kit and its downstream substrates by GATA-1 inhibits cell proliferation during erythroid maturation. Mol Cellular Biol 25, 6747–6759CrossRefGoogle Scholar
  59. Orkin, S.H., and Zon, L.I. (2008). Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644CrossRefPubMedPubMedCentralGoogle Scholar
  60. Peng, G., Suo, S., Chen, J., Chen, W., Liu, C., Yu, F., Wang, R., Chen, S., Sun, N., Cui, G., et al. (2016). Spatial transcriptome for the molecular annotation of lineage fates and cell identity in Mid-gastrula mouse embryo. Dev Cell 36, 681–697CrossRefPubMedGoogle Scholar
  61. Porayette, P., and Paulson, R.F. (2008). BMP4/Smad5 dependent stress erythropoiesis is required for the expansion of erythroid progenitors during fetal development. Dev Biol 317, 24–35CrossRefPubMedPubMedCentralGoogle Scholar
  62. Rybtsov, S., Ivanovs, A., Zhao, S., and Medvinsky, A. (2016). Concealed expansion of immature precursors underpins acute burst of adult HSC activity in foetal liver. Development 143, 1284–1289CrossRefPubMedPubMedCentralGoogle Scholar
  63. Swain, A., Inoue, T., Tan, K.S., Nakanishi, Y., and Sugiyama, D. (2014). Intrinsic and extrinsic regulation of mammalian hematopoiesis in the fetal liver. Histol Histopathol 29, 1077–1082PubMedGoogle Scholar
  64. Szilvassy, S.J., Meyerrose, T.E., Ragland, P.L., and Grimes, B. (2001). Differential homing and engraftment properties of hematopoietic progenitor cells from murine bone marrow, mobilized peripheral blood, and fetal liver. Blood 98, 2108–2115CrossRefPubMedGoogle Scholar
  65. Szpinda, M., Paruszewska-Achtel, M., Woźniak, A., Badura, M., Mila-Kierzenkowska, C., and Wiśniewski, M. (2015). Three-dimensional growth dynamics of the liver in the human fetus. Surg Radiol Anat 37, 439–448CrossRefPubMedPubMedCentralGoogle Scholar
  66. Takebe, T., Sekine, K., Suzuki, Y., Enomura, M., Tanaka, S., Ueno, Y., Zheng, Y.W., and Taniguchi, H. (2012). Self-organization of human hepatic organoid by recapitulating organogenesis in vitro. Transplant Proc 44, 1018–1020CrossRefPubMedGoogle Scholar
  67. Tang, Y., Peitzsch, C., Charoudeh, H.N., Cheng, M., Chaves, P., Jacobsen, S.E.W., and Sitnicka, E. (2012). Emergence of NK-cell progenitors and functionally competent NK-cell lineage subsets in the early mouse embryo. Blood 120, 63–75CrossRefPubMedGoogle Scholar
  68. Treutlein, B., Brownfield, D.G., Wu, A.R., Neff, N.F., Mantalas, G.L., Espinoza, F.H., Desai, T.J., Krasnow, M.A., and Quake, S.R. (2014). Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq. Nature 509, 371–375CrossRefPubMedPubMedCentralGoogle Scholar
  69. Williams, D.E., Eisenman, J., Baird, A., Rauch, C., Van Ness, K., March, C.J., Park, L.S., Martin, U., Mochizukl, D.Y., Boswell, H.S., et al. (1990). Identification of a ligand for the c-kit proto-oncogene. Cell 63, 167–174CrossRefPubMedGoogle Scholar
  70. Xie, Y., Li, Y., and Kong, Y. (2014). OPN induces FoxM1 expression and localization through ERK 1/2 AKT, and p38 signaling pathway in HEC-1A cells. Int J Mol Sci 15, 23345–23358CrossRefPubMedPubMedCentralGoogle Scholar
  71. You, L., Li, L., Zou, J., Yan, K., Belle, J., Nijnik, A., Wang, E., and Yang, X.J. (2016). BRPF1 is essential for development of fetal hematopoietic stem cells. J Clin Investig 126, 3247–3262CrossRefPubMedGoogle Scholar
  72. Zayas, J., Spassov, D.S., Nachtman, R.G., and Jurecic, R. (2008). Murine hematopoietic stem cells and multipotent progenitors express truncated intracellular form of c-kit receptor. Stem Cells Dev 17, 343–354CrossRefPubMedPubMedCentralGoogle Scholar
  73. Zeigler, F.C., Bennett, B.D., Jordan, C.T., Spencer, S.D., Baumhueter, S., Carroll, K.J., Hooley, J., Bauer, K., and Matthews, W. (1994). Cellular and molecular characterization of the role of the flk-2/flt-3 receptor tyrosine kinase in hematopoietic stem cells. Blood 84, 2422–2430PubMedGoogle Scholar
  74. Zhang, C.C., Kaba, M., Ge, G., Xie, K., Tong, W., Hug, C., and Lodish, H. F. (2006). Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nat Med 12, 240–245CrossRefPubMedPubMedCentralGoogle Scholar
  75. Zhang, C.C., and Lodish, H.F. (2004). Insulin-like growth factor 2 expressed in a novel fetal liver cell population is a growth factor for hematopoietic stem cells. Blood 103, 2513–2521CrossRefPubMedGoogle Scholar
  76. Zhao, X., Gao, F., Zhang, X., Wang, Y., Xu, L., Liu, K., Zhao, X., Chang, Y., Wei, H., Chen, H., et al. (2016). Improved clinical outcomes of rhGCSF-mobilized blood and marrow haploidentical transplantation compared to propensity score-matched rhG-CSF-primed peripheral blood stem cell haploidentical transplantation: a multicenter study. Sci China Life Sci 59, 1139–1148CrossRefPubMedGoogle Scholar
  77. Zhao, Y., Zhou, J., Liu, D., Dong, F., Cheng, H., Wang, W., Pang, Y., Wang, Y., Mu, X., Ni, Y., et al. (2015). ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver. Blood 126, 2383–2391CrossRefPubMedPubMedCentralGoogle Scholar
  78. Zheng, J., Umikawa, M., Cui, C., Li, J., Chen, X., Zhang, C., Huynh, H.D., Hyunh, H., Kang, X., Silvany, R., et al. (2012). Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485, 656–660CrossRefPubMedPubMedCentralGoogle Scholar
  79. Zhou, B.O., Yu, H., Yue, R., Zhao, Z., Rios, J.J., Naveiras, O., and Morrison, S.J. (2017). Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat Cell Biol 19, 891–903.CrossRefPubMedPubMedCentralGoogle Scholar

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© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.College of Life SciencesHebei UniversityBaodingChina
  2. 2.State Key Laboratory of Membrane Biology, Institute of ZoologyChinese Academy of SciencesBeijingChina
  3. 3.University of Chinese Academy of SciencesBeijingChina

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