title: Medium conditioned with mesenchymal stromal cell-derived osteoblasts improves the expansion and engraftment properties of cord blood progenitors.
abstract: Strategies to enhance the expansion of umbilical cord blood hematopoietic stem and progenitor cells (HSPCs) are crucial to enable their widespread application to adults and to overcome important limitations, such as delayed engraftment. Osteoblasts regulate HSPCs under steady-state and also under stress conditions, when HSPCs undergo numerous cycles of expansion. We hypothesized that osteoblasts could provide better stimulation for the expansion of multipotent HSPCs and subsequent hematopoietic recovery than mesenchymal stromal cells. Hence, we assessed the growth and engraftment modulatory activities of mesenchymal stromal cell-derived osteoblasts (M-OSTs) on hematopoietic progenitors. Mesenchymal stromal cells and M-OSTs favored the maintenance of CD34(+) cells. The expansion of cord blood CD34(+) cells and myeloid progenitors was highest in cultures supplemented with unfiltered M-OST-conditioned medium (M-OST CM). In addition, increased expression of cell surface receptors important for the homing of progenitors to the bone marrow, C-X-C chemokine receptor type 4 and lymphocyte function-associated antigen 1, was observed in CM-based cultures. Additionally, M-OST CM positively modulated the engraftment properties of expanded progenitors. Most notably, although human platelet levels remained steady in the first 2 weeks in mice transplanted with HSPCs expanded in standard medium, levels in mice transplanted with M-OST CM HSPCs rose continuously. Consistent with this, short-term human progenitor reconstitution was consistently greater in M-OST recipients. Finally, cytokine array-based profiling revealed increases in insulin-like growth factor binding protein 2, chemokines, and myeloid stimulating cytokines in M-OST CM. In conclusion, this study suggests that M-OSTs represent a new underappreciated source of feeder cells for the expansion of HSPCs with enhanced thrombopoietic activity.
authors.affiliation: Héma-Québec, Research and Development, Quebec City, Canada.
authors.forename: Nellie
authors.initials: N
authors.lastname: Dumont
authors.affiliation: Héma-Québec, Research and Development, Quebec City, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Boyer
authors.affiliation: Héma-Québec, Research and Development, Quebec City, Canada.
authors.forename: Hélène
authors.initials: H
authors.lastname: Émond
authors.affiliation: Héma-Québec, Research and Development, Quebec City, Canada; Laboratory for Biomaterials and Bioengineering, Department of Mining-Metallurgical and Materials Engineering & University Hospital Research Center, Laval University, Quebec City, Canada.
authors.forename: Betül
authors.initials: B
authors.lastname: Celebi-Saltik
authors.affiliation: Canadian Blood Services, Center for Innovation, Ottawa, Canada.
authors.forename: Roya
authors.initials: R
authors.lastname: Pasha
authors.affiliation: Héma-Québec, Research and Development, Quebec City, Canada; Department of Biochemistry, Microbiology and Bioinformatics, Laval University, Quebec City, Canada.
authors.forename: Renée
authors.initials: R
authors.lastname: Bazin
authors.affiliation: Laboratory for Biomaterials and Bioengineering, Department of Mining-Metallurgical and Materials Engineering & University Hospital Research Center, Laval University, Quebec City, Canada.
authors.forename: Diego
authors.initials: D
authors.lastname: Mantovani
authors.affiliation: Centre de Recherche Hôpital Maisonneuve-Rosemont, Montreal, Canada; Division of Hematology-Oncology, Department of Medicine, University of Montréal, Montreal, Canada.
authors.forename: Denis-Claude
authors.initials: DC
authors.lastname: Roy
authors.affiliation: Héma-Québec, Research and Development, Quebec City, Canada; Department of Biochemistry, Microbiology and Bioinformatics, Laval University, Quebec City, Canada; Canadian Blood Services, Center for Innovation, Ottawa, Canada. Electronic address: nicolas.pineault@blood.ca.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pineault
mesh_terms: D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned