A pluripotent stem cell model of Emberger syndrome reveals reduced lymphatic endothelial differentiation

Brouillard P, Boon L, Vikkula M. Genetics of lymphatic anomalies. J Clin Invest. 2014;124:898–904.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004;5:74–80.

Article  CAS  PubMed  Google Scholar 

Spinner MA, Sanchez LA, Hus AP, Shaw PA, Zerbe CS, Valvl KR, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123:809–21.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Emberger JM, Navarro M, Dejean M, Izarn P. Deaf-mutism, lymphedema of the lower limbs and hematological abnormalities (acute leukemia, cytopenia) with autosomal dominant transmission. J Genet Hum. 1979;27:237–45.

CAS  PubMed  Google Scholar 

Mansour S, Connell F, Steward C, Ostergaard P, Brice G, Smithson S, et al. Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases. Am J Med Genet A. 2020;152A:2287–96.

Article  Google Scholar 

Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet. 2011;43:929–31.

Article  CAS  PubMed  Google Scholar 

Kazenwadel J, Betterman KL, Chong CE, Stokes PH, Lee YK, Secker GA, et al. GATA2 is required for lymphatic vessel valve development and maintenance. J Clin Invest. 2015;125:2979–94.

Article  PubMed  PubMed Central  Google Scholar 

Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S, Tsai MJ, et al. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. 2007;21:2422–32.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Oliver G, Srinivasan RS. Endothelial cell plasticity: how to become and remain a lymphatic endothelial cell. Development. 2010;137:363–72.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Escobedo N, Oliver G. Lymphangiogenesis: origin, specification, and cell fate determination. Ann Rev Cell Dev Biol. 2016;32:677–91.

Article  CAS  Google Scholar 

Tsai FY, Keller G, Kuo FC, Weiss M, Chen J, Rosenblatt M, et al. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature. 1994;371:221–6.

Article  CAS  PubMed  Google Scholar 

Gumina RJ, Kirschbaum NE, Piotrowski K, Newman PJ. Characterization of the human platelet/endothelial cell adhesion molecule-1 promoter: identification of a GATA-2 binding element required for optimal transcriptional activity. Blood. 1997;89:1260–9.

Article  CAS  PubMed  Google Scholar 

Kazenwadel J, Secker GA, Liu YJ, Rosenfeld JA, Wildin RS, Cuellar-Rodriguez J, et al. Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood. 2011;119:1283–91.

Article  PubMed  Google Scholar 

Lim KC, Hosoya T, Brandt W, Ku CJ, Hosoya-Ohmura S, Camper SA, et al. Conditional Gata2 inactivation results in HSC loss and lymphatic mispatterning. J Clin Invest. 2012;122:3705–17.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kazenwadel J, Venugopal P, Oszmiana A, Toubia J, Arriola-Martinez L, Panara V, et al. A Prox1 enhancer represses haematopoiesis in the lymphatic vasculature. Nature. 2023;614:343–8.

Article  CAS  PubMed  Google Scholar 

Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

Article  CAS  PubMed  Google Scholar 

Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.

Article  CAS  PubMed  Google Scholar 

Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.

Article  CAS  PubMed  Google Scholar 

Kono T, Kubo H, Shimazu C, Ueda Y, Takahashi M, Yanagi K, et al. Differentiation of lymphatic endothelial cells from embryonic stem cells on OP9 stromal cells. Arterioscler Thromb Vasc Biol. 2006;26:2070–6.

Article  CAS  PubMed  Google Scholar 

Niwa A, Heike T, Umeda K, Oshima K, Kato I, Sakai H, et al. A novel serum-free monolayer culture for orderly hematopoietic differentiation of human pluripotent cells via mesodermal progenitors. PLoS One. 2011;6: e22261.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Morishima T, Watanabe K, Niwa A, Hirai H, Saida S, Tanaka T, et al. Genetic correction of HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis. Haematologica. 2014;99:19–27.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Suzuki NM, Niwa A, Yabe M, Hira A, Okada C, Amano N, et al. Pluripotent cell models of fanconi anemia identify the early pathological defect in human hemoangiongenic progenitors. Stem Cells Trans Med. 2015;4:333–8.

Article  CAS  Google Scholar 

Hamabata T, Umeda K, Kouzuki K, Tanaka T, Daifu T, Nodomi S, et al. Pluripotent stem cells model of Shwachman-Diamond syndrome reveals apoptotic predisposition of hemoangiogenic progenitors. Sci Rep. 2009;10:14859.

Article  Google Scholar 

Saida S, Umeda K, Yasumi T, Matsumoto A, Kato I, Hiramatsu H, et al. Successful reduced-intensity stem cell transplantation for GATA2 deficiency before progression of advanced MDS. Pediatr Transplant. 2016;20:333–6.

Article  CAS  PubMed  Google Scholar 

Okita K, Yamakawa T, Matsumura Y, Sato Y, Amano N, Watanabe A, et al. An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cord blood and peripheral blood cells. Stem Cells. 2013;31:458–66.

Article  CAS  PubMed  Google Scholar 

Yoshinaga D, Baba S, Makiyama T, Shibata H, Hirata T, Akagi K, et al. Phenotype-based high-throughput classification of long QT syndrome subtypes using human induced pluripotent stem cells. Stem Cell Reports. 2019;13:394–404.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Shiba T, Tanaka T, Ida H, Watanabe M, Nakaseko H, Osawa M, et al. Functional evaluation of the pathological significance of MEFV variants using induced pluripotent stem cell-derived macrophages. J Allergy Clin Immunol. 2019;144:1438–41.

Article  PubMed  Google Scholar 

Lee SJ, Park C, Lee JY, Kim S, Kwon PJ, Kim W, et al. Generation of pure lymphatic endothelial cells from human pluripotent stem cells and their therapeutic effects on wound repair. Sci Rep. 2015;5:11019.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wlodarski MW, Hirabayashi S, Pastor V, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127:1387–97.

Article  CAS  PubMed  Google Scholar 

Rufaihah AJ, Huang NF, Kim J, Herold J, Volz KS, Park TS, et al. Human induced pluripotent stem cell-derived endothelial cells exhibit functional heterogeneity. Am J Transl Res. 2013;5:21–35.

CAS  PubMed  PubMed Central  Google Scholar 

Hong M, Jung E, Yang S, Jung W, Seong YJ, Park E, et al. Efficient assessment of developmental, surgical and pathological lymphangiogenesis using a lymphatic reporter mouse and its embryonic stem cells. PLoS One. 2016;11: e0157126.

Comments (0)

No login
gif