Thor ContributionsConceived and designed the experiments: IMMNV MESA SS. Performed the experiments: IMMNV MESA MDSR MPL LFAV. Analyzed the information: IMMNV MESA MPL. Contributed reagents/materials/analysis tools: SS MESA. Wrote the paper: IMMNV MESA SS.
NIH Public AccessAuthor ManuscriptNat Med. Author manuscript; available in PMC 2009 November 2.Published in final edited type as: Nat Med. 2006 February ; 12(two): 24045. doi:ten.1038/nm1342.DNA Methyltransferase drug 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 TAM Receptor drug Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.2Departmentof Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.3Divisionof Respiratory Diseases, Children’s Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.4HarvardMedical College, 25 Shattuck Street, Boston, Massachusetts 02115, USA.AbstractSuccessful ex vivo expansion of hematopoietic stem cells (HSCs) would drastically advantage the therapy of disease along with the understanding of crucial questions of stem cell biology. Here we show, using microarray studies, that the HSC-supportive mouse fetal liver CD3+ cells specifically express the proteins angiopoietin-like two (Angptl2) and angiopoietin-like 3 (Angptl3). We observed a 24- or 30fold net expansion of long-term HSCs by reconstitution analysis when we cultured highly enriched HSCs for 10 days in the presence of Angptl2 or Angptl3 together with saturating levels of other growth variables. The coiled-coil domain of Angptl2 was capable of stimulating expansion of HSCs. Furthermore, angiopoietin-like 5, 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 kinds, type the basis of bone marrow transplantation for remedy of cancers and hematopoietic disorders1, and are also a promising cell target for gene therapies that can potentially treat a broad selection of human diseases2. Development of those vital clinical applications of HSCs is tremendously hampered by the lack of understanding from the extracellular and intracellular signals that govern their fates as well as by the difficulty in carrying out ex vivo expansion of these cells. Several attempts happen to be created to increase the amount of long-term HSCs in culture3,four. The usage of stromal cell lines or combinations of cytokines have resulted in considerable selfrenewal of mouse HSCs assayed four weeks just after transplant, and have led to as a lot as a sixfold enhance in mouse long-term HSC activity in culture5-9. The introduction of exogenous transcription components can expand HSCs extra substantially10-12, though gene transduction of HSCs may very well be hazardous to men and women in clinical settings2.2006 Nature Publishing Group Correspondence ought to be addressed to H.F.L. ([email protected]).. Note: Supplementary data is out there around the Nature Medicine internet site. COMPETING INTERESTS STATEMENT The authors declare that they have no competing monetary interests.Zhang et al.PageBecause fetal liver HSCs undergo marked expansion in the course of embryonic development, we hypothesized that particular fetal liver Lineage-positive cells may produce protein(s) that supp.