{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:16:51Z","timestamp":1790810211972,"version":"4.1.0"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2014,5,30]],"date-time":"2014-05-30T00:00:00Z","timestamp":1401408000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2014,5,30]],"date-time":"2014-05-30T00:00:00Z","timestamp":1401408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Stem Cell Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>Insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs) and angiopoietin-like proteins (ANGPTLs) can enhance the <jats:italic>ex vivo<\/jats:italic> expansion of hematopoietic stem cells (HSCs) when used with a standard cytokine cocktail of stem cell factor (SCF), thrombopoietin (TPO) and FLT3 ligand (FL). In order to determine the optimal dose and combination of IGFs, IGFBPs and ANGPTLs, serial dilution and full permutation of IGFBP1, IGFBP2, IGF2 and ANGPTL3 were applied on a cryopreserved umbilical cord blood mononuclear cell (UCB-MNC) <jats:italic>ex vivo<\/jats:italic> expansion system.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>In this system, 4\u2009\u00d7\u200910<jats:sup>5<\/jats:sup> cells\/ml of UCB-MNCs were inoculated in serum-free Stemspan\u00ae medium (Stemcell technologies, vancouver, BC, Canada) supplied with standard basal cytokine combination of 100 ng\/ml SCF, 50 ng\/ml FL and 100 ng\/ml TPO and supported by a bone marrow mesenchymal stromal cell layer.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>Paradoxically, experiment results showed that the highest expansion of CD34<jats:sup>+<\/jats:sup>CD38<jats:sup>\u2212<\/jats:sup>CD90<jats:sup>+<\/jats:sup> primitive progenitor was stimulated by cytokine combination of SCF\u2009+\u2009TPO\u2009+\u2009FL\u2009+\u2009IGFBP1\u2009+\u2009IGFBP2\u2009+\u2009ANGPTL3 at a low dose of 15 ng\/ml IGFBP1 and 20 ng\/ml IGFBP2 and ANGPTL3. This <jats:italic>ex vivo<\/jats:italic> expansion was further validated in 8-week-old to 10-week-old nonobese diabetic\/severe combined immunodeficiency interleukin 2 gamma chain null (NOD\/SCID-IL2R\u03b3<jats:sup>\u2212\/\u2212<\/jats:sup>) mice. Limiting dilution assay showed excellent correlation between the HSC <jats:italic>ex vivo<\/jats:italic> surface marker of CD34<jats:sup>+<\/jats:sup>CD38<jats:sup>\u2212<\/jats:sup>CD90<jats:sup>+<\/jats:sup> and the <jats:italic>in vivo<\/jats:italic> competitive repopulating unit (CRU) functional assay.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusion<\/jats:title>\n                        <jats:p>IGFBP1, IGFBP2, IGF2 and ANGPTL3 can stimulate the expansion of CD34<jats:sup>+<\/jats:sup>CD38<jats:sup>\u2212<\/jats:sup>CD90<jats:sup>+<\/jats:sup> primitive progenitor at low dose. The optimal combination comprises IGFBP1, IGFBP2 and ANGPTL3 together with the standard cytokine cocktail of SCF, FL and TPO. The CD34<jats:sup>+<\/jats:sup>CD38<jats:sup>\u2212<\/jats:sup>CD90<jats:sup>+<\/jats:sup> phenotype can serve as a surrogate <jats:italic>ex vivo<\/jats:italic> surface marker for HSCs due to consistency with the <jats:italic>in vivo<\/jats:italic> CRU functional assay.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/scrt460","type":"journal-article","created":{"date-parts":[[2014,5,30]],"date-time":"2014-05-30T09:07:59Z","timestamp":1401440879000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Low-dose insulin-like growth factor binding proteins 1 and 2 and angiopoietin-like protein 3 coordinately stimulate ex vivo expansion of human umbilical cord blood hematopoietic stem cells as assayed in NOD\/SCID gamma null mice"],"prefix":"10.1186","volume":"5","author":[{"given":"Xiubo","family":"Fan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence PH","family":"Gay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca WI","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justina ML","family":"Ang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pat PY","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudipto","family":"Bari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William YK","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,5,30]]},"reference":[{"key":"366_CR1","doi-asserted-by":"publisher","first-page":"682","DOI":"10.3109\/08880018.2011.599477","volume":"28","author":"YH Noh","year":"2011","unstructured":"Noh YH, Yim YS, Kim DH, Lee MW, Kim DS, Kim HR, Lee SH, Chueh HW, Choi SJ, Oh WI, Yang YS, Jung HL, Yoo KH, Sung KW, Koo HH: Correlation between chemokines released from umbilical cord blood-derived mesenchymal stem cells and engraftment of hematopoietic stem cells in nonobese diabetic\/severe combined immunodeficient (NOD\/SCID) mice. 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