These studies provide a mechanistic basis by which d7EB cells prevent sepsis-induced lung inflammatory injury. hESC-derived d7EB cells responsible for the protective phenotype were identified and found to be enriched in two cell surface markers, ACE and KDR. It was also demonstrated that the population consisting of ACEϩKDRϩ and ACEϩKDRϪ progenitor cells gave rise in culture to endothelial and hematopoietic colonies, respectively. In addition, the ACE-expressing cells expressed TLR4, the receptor sensing LPS, and produced NO. In contrast, ACEϪ cells did not exhibit these char-acteristics. The functional importance of these observations was reinforced by the ability of ACEϩ fractions of d7EB cells to modulate the inflammatory cytokine production profile of CD11bϩ host cells through direct cellcell interaction. ACE is constitutively expressed on the surface of endothelial and hematopoietic precursors, 41, 42 and ACE has been identified as a marker of hematopoietic stem cells present at all stages in the ontogeny of the human hematopoietic system 43 and as a novel marker of hemangioblasts differentiating from hESCs. 28 Evidence also points to an important role of ACE in sepsis. ACE knockout mice exhibited improved lung injury scores after acid aspiration, endotoxin challenge, and peritoneal sepsis. 44 Cohort studies in humans have shown a correlation between ACE polymorphisms and susceptibility to and death from adult respiratory distress syndrome, 45 and decreased plasma concentrations of ACE have been observed in patients with adult respiratory distress syndrome and sepsis. 46 A close homologue of ACE, ACE 2, has been identified as a key factor in protection from adult respiratory distress syndrome, and it also functions as a critical in vivo receptor for severe acute respiratory syndrome. 47, 48 A limitation of the present study is that the immunologic properties of human progenitor cells were studied in a xenograft model, introducing biases related to cross-species barriers. However, there is no reason to believe that species incompatibility affects the validity of the proposed mechanism, which involves interaction with host CD11bϩ cells and modulation of NO production. Human cells were not acutely eliminated by the immune-competent mice because cells were detected in lungs for 24 hours after injection. These data are in accord with observations in syngeneic mouse mesenchymal stem cells 6 and may be related to the immunosuppressive nature of the human cells. 49 It is likely, however, that some degree of immunosuppression will be required for longer term xenotransplantation studies. 50 Although, to our knowledge, the present study is the first to describe the function of mesodermally differentiated hESCs in a model of lethal sepsis and lung injury, other studies have used bone marrow mesenchymal stromal cells in similar models. 4,6 -11 These studies demonstrated an anti-inflammatory benefit of these cells but showed variable effects on the production of anti-inflammatory and pro-inflammatory cytokines. In a polymicrobial sepsis model, the beneficial effect of bone marrow stem cells was attributed to stem cell-induced production of IL-10 by host macrophages, 6 sphingosine-1-phosphate production by stem cells, 11 and homing of stem cells to lungs through integrin expression. 7,11 hESC-derived progenitor cells represent a much earlier developmental stage than bone marrow mesenchymal stem cells, and they have demonstrated ability to differentiate into niche-specific mature cells, a characteristic that distinguishes them from adult mesenchymal stromal cells. Although the importance of the interaction of hESC-derived cells with host CD11bϩ cells and the association of ACE expression with the protective phenotype were observed, factors such as homing to a niche and the engraftment potential of hESC-derived cells that may also be impor-tant in the observed protection cannot be ruled out. Findings of the present study demonstrate that d7EB cells, a population of hESC-derived progenitor cells, constitute a novel immunomodulatory cell population with therapeutic potential in sepsis that may have clinical application in cell-based therapy. Wide Prevalence of Heterosubtypic Broadly Neutralizing Human Anti-Influenza A Antibodies (See the editorial commentary by Donis and Cox, on pages 1010–1012.) Background. Lack of life-long immunity against influenza viruses represents a major global health care problem with profound medical and economic consequences. A greater understanding of the broad-spectrum “heterosubtypic” neutralizing human antibody (BnAb) response to influenza should bring us closer toward a universal influenza vaccine. Methods. Serum samples obtained from 77 volunteers in an H5N1 vaccine study were analyzed for cross-reactive antibodies (Abs) against both subtype hemagglutinins (HAs) and a highly conserved pocket on the HA stem of Group 1 viruses. Cross-reactive Abs in commercial intravenous immunoglobulin were affinity purified using H5-coupled beads followed by step-wise monoclonal antibody competition or acid elution. Enzyme-linked immunosorbent assays were used to quantify cross-binding, and neutralization activity was determined with HA-pseudotyped viruses. Results. Prevaccination serum samples have detectable levels of heterosubtypic HA binding activity to both Group 1 and 2 influenza A viruses, including subtypes H5 and H7, respectively, to which study subjects had not been vaccinated. Two different populations of Broadly neutralizing Abs (BnAbs) were purified from intravenous immunoglobulin by H5 beads: ∼0.01% of total immunoglobulin G can bind to HAs from both Group 1 and 2 and neutralize H1N1 and H5N1 viruses; ∼0.001% is F10-like Abs directed against the HA stem pocket on Group 1 viruses. Conclusion. These data—to our knowledge, for the first time—quantitatively show the presence, albeit at low levels, of two populations of heterosubtypic BnAbs against influenza A in human serum. These observations warrant further investigation to determine their origin, host polymorphism(s) that may affect their expression levels and how to boost these BnAb responses by vaccination to reach sustainable protective levels. Influenza remains a major medical problem and is a constant threat to human health. Of the 3 influenza virus genera (A-C), influenza A is generally associated with more severe disease and is further subtyped by 2 surface proteins, hemagglutinin (HA) and neuraminidase (NA). Various combinations of the 16 HA (2 phylogenetic groups) and 9 NA subtypes define all subtypes of influenza A viruses. The Group 1 HA subtypes are H1, H2, H5, H6, H8, H9, H11, H12, H13, and H16; the Group 2 HA subtypes are H3, H4, H7, H10, H14, and H15. Seasonal viruses, such as influenza A H1N1 (Group 1) and H3N2 (Group 2), and influenza B viruses cause infection in 5%-15% of the population worldwide and 250,000-500,000 deaths annually. In addition to frequent annual epidemics, influenza viruses periodically cause pandemics, the most recent example being the 2009 pandemic caused by the swine-origin H1N1/2009 influenza virus.