Thor ContributionsConceived and created the experiments: IMMNV MESA SS. Performed the experiments: IMMNV MESA MDSR

Thor ContributionsConceived and created the experiments: IMMNV MESA SS. Performed the experiments: IMMNV MESA MDSR MPL LFAV. Analyzed the data: IMMNV MESA MPL. Contributed reagents/materials/analysis tools: SS MESA. Wrote the paper: IMMNV MESA SS.
NIH Public AccessAuthor ManuscriptNat Med. Author manuscript; out there in PMC 2009 November two.Published in final edited form as: Nat Med. 2006 February ; 12(two): 24045. doi:10.1038/nm1342.Ubiquitin-Specific Peptidase 20 Proteins site NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptAngiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cellsCheng Cheng Zhang1, Megan Kaba1, Guangtao Ge1, Kathleen Xie1, Wei Tong1, Christopher Hug1,3, and Harvey F Lodish1,4 1Whitehead Institute for Biomedical Study, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.2Departmentof FGFR-4 Proteins Recombinant Proteins Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.3Divisionof Respiratory Ailments, Children’s Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.4HarvardMedical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.AbstractSuccessful ex vivo expansion of hematopoietic stem cells (HSCs) would greatly benefit the therapy of disease and the understanding of essential queries of stem cell biology. Here we show, making use of microarray studies, that the HSC-supportive mouse fetal liver CD3+ cells specifically express the proteins angiopoietin-like two (Angptl2) and angiopoietin-like three (Angptl3). We observed a 24- or 30fold net expansion of long-term HSCs by reconstitution evaluation when we cultured hugely enriched HSCs for ten days inside the presence of Angptl2 or Angptl3 with each other with saturating levels of other development elements. The coiled-coil domain of Angptl2 was capable of stimulating expansion of HSCs. In addition, angiopoietin-like five, angiopoietin-like 7 and microfibril-associated glycoprotein four also supported expansion of HSCs in culture. HSCs, defined by their capability to self-renew and to differentiate into all blood cell forms, kind the basis of bone marrow transplantation for treatment of cancers and hematopoietic disorders1, and are also a promising cell target for gene therapies that could potentially treat a broad number of human diseases2. Development of those significant clinical applications of HSCs is greatly hampered by the lack of understanding with the extracellular and intracellular signals that govern their fates at the same time as by the difficulty in carrying out ex vivo expansion of these cells. Many attempts have already been created to enhance the number of long-term HSCs in culture3,four. The use of stromal cell lines or combinations of cytokines have resulted in considerable selfrenewal of mouse HSCs assayed 4 weeks just after transplant, and have led to as considerably as a sixfold raise in mouse long-term HSC activity in culture5-9. The introduction of exogenous transcription variables can expand HSCs additional substantially10-12, though gene transduction of HSCs can be risky to men and women in clinical settings2.2006 Nature Publishing Group Correspondence should be addressed to H.F.L. ([email protected]).. Note: Supplementary information is offered around the Nature Medicine site. COMPETING INTERESTS STATEMENT The authors declare that they have no competing financial interests.Zhang et al.PageBecause fetal liver HSCs undergo marked expansion in the course of embryonic improvement, we hypothesized that certain fetal liver Lineage-positive cells may well produce protein(s) that supp.