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While many of the yolk sac\u2013derived populations are transient, specific immune cell progeny seed developing tissues, where they function into adult life. To access the human equivalent of these lineages, we modeled yolk sac hematopoietic development using pluripotent stem cell differentiation. Here, we show that the combination of Activin A, BMP4, and FGF2 induces a population of KDR+CD235a\/b+ mesoderm that gives rise to the spectrum of erythroid, myeloid, and T lymphoid lineages characteristic of the mouse yolk sac hematopoietic programs, including the V\u03b42+ subset of \u03b3\/\u03b4 T cells that develops early in the human embryo. Through clonal analyses, we identified a multipotent hematopoietic progenitor with erythroid, myeloid, and T lymphoid potential, suggesting that the yolk sac EMP and lymphoid lineages may develop from a common progenitor.<\/jats:p>","DOI":"10.1084\/jem.20211924","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T02:22:49Z","timestamp":1638325369000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":66,"title":["Modeling human yolk sac hematopoiesis with pluripotent stem cells"],"prefix":"10.1084","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4905-7943","authenticated-orcid":true,"given":"Michael H.","family":"Atkins","sequence":"first","affiliation":[{"name":"McEwen Stem Cell Institute, University Health Network, Toronto, Ontario, Canada 1"},{"name":"Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9621-3793","authenticated-orcid":true,"given":"Rebecca","family":"Scarf\u00f2","sequence":"additional","affiliation":[{"name":"San Raffaele Telethon Institute for Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare, San Raffaele Scientific Institute, Milan, Italy 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2372-6109","authenticated-orcid":true,"given":"Kathleen E.","family":"McGrath","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1290-4384","authenticated-orcid":true,"given":"Donghe","family":"Yang","sequence":"additional","affiliation":[{"name":"McEwen Stem Cell Institute, University Health Network, Toronto, Ontario, Canada 1"},{"name":"Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7324-1049","authenticated-orcid":true,"given":"James","family":"Palis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3283-8943","authenticated-orcid":true,"given":"Andrea","family":"Ditadi","sequence":"additional","affiliation":[{"name":"San Raffaele Telethon Institute for Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare, San Raffaele Scientific Institute, Milan, Italy 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9309-9297","authenticated-orcid":true,"given":"Gordon M.","family":"Keller","sequence":"additional","affiliation":[{"name":"McEwen Stem Cell Institute, University Health Network, Toronto, Ontario, Canada 1"},{"name":"Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"2023072812513842100_bib1","doi-asserted-by":"publisher","first-page":"2349","DOI":"10.1182\/blood-2014-09-599423","article-title":"\u03b3\u03b4 T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-\u03b1\u03b2+\/CD19+ lymphocytes","volume":"125","author":"Airoldi","year":"2015","journal-title":"Blood."},{"key":"2023072812513842100_bib2","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1038\/s41586-020-2316-7","article-title":"Deciphering human macrophage development at single-cell resolution","volume":"582","author":"Bian","year":"2020","journal-title":"Nature."},{"key":"2023072812513842100_bib3","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.stem.2013.08.012","article-title":"Lymphomyeloid contribution of an immune-restricted progenitor emerging prior to definitive hematopoietic stem cells","volume":"13","author":"B\u00f6iers","year":"2013","journal-title":"Cell Stem Cell."},{"key":"2023072812513842100_bib4","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.618164","article-title":"Prenatal origin of pediatric leukemia: lessons from hematopoietic development","volume":"8","author":"Cazzola","year":"2021","journal-title":"Front. 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