title: Bone marrow osteoblast damage by chemotherapeutic agents.
abstract: Hematopoietic reconstitution, following bone marrow or stem cell transplantation, requires a microenvironment niche capable of supporting both immature progenitors and stem cells with the capacity to differentiate and expand. Osteoblasts comprise one important component of this niche. We determined that treatment of human primary osteoblasts (HOB) with melphalan or VP-16 resulted in increased phospho-Smad2, consistent with increased TGF-β1 activity. This increase was coincident with reduced HOB capacity to support immature B lineage cell chemotaxis and adherence. The supportive deficit was not limited to committed progenitor cells, as human embryonic stem cells (hESC) or human CD34+ bone marrow cells co-cultured with HOB pre-exposed to melphalan, VP-16 or rTGF-β1 had profiles distinct from the same populations co-cultured with untreated HOB. Functional support deficits were downstream of changes in HOB gene expression profiles following chemotherapy exposure. Melphalan and VP-16 induced damage of HOB suggests vulnerability of this critical niche to therapeutic agents frequently utilized in pre-transplant regimens and suggests that dose escalated chemotherapy may contribute to post-transplantation hematopoietic deficits by damaging structural components of this supportive niche.
authors.affiliation: Cancer Cell Biology Program, School of Medicine, West Virginia University, Morgantown, West Virginia, United States of America.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Rellick
authors.forename: Heather
authors.initials: H
authors.lastname: O'Leary
authors.forename: Debbie
authors.initials: D
authors.lastname: Piktel
authors.forename: Cheryl
authors.initials: C
authors.lastname: Walton
authors.forename: James E
authors.initials: JE
authors.lastname: Fortney
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Akers
authors.forename: Karen H
authors.initials: KH
authors.lastname: Martin
authors.forename: James
authors.initials: J
authors.lastname: Denvir
authors.forename: Goran
authors.initials: G
authors.lastname: Boskovic
authors.forename: Donald A
authors.initials: DA
authors.lastname: Primerano
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Vos
authors.forename: Nathanael
authors.initials: N
authors.lastname: Bailey
authors.forename: Marieta
authors.initials: M
authors.lastname: Gencheva
authors.forename: Laura F
authors.initials: LF
authors.lastname: Gibson
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008558:Melphalan / Q000009:adverse effects; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D008558:Melphalan