title: Bone Marrow-Derived Mesenchymal Stromal Cells from Patients with Sickle Cell Disease Display Intact Functionality.
abstract: Hematopoietic cell transplantation (HCT) is the only cure for sickle cell disease (SCD), but engraftment remains challenging in patients lacking matched donors. Infusion of mesenchymal stromal cells (MSCs) at the time of HCT may promote hematopoiesis and ameliorate graft-versus-host disease. Experimental murine models suggest MSC major histocompatibility complex compatibility with recipient impacts their in vivo function, suggesting autologous MSCs could be superior to third-party MSCs for promoting HCT engraftment. Here we tested whether bone marrow (BM)-derived MSCs from SCD subjects have comparable functionality compared with MSCs from healthy volunteers. SCD MSC doubling time and surface marker phenotype did not differ significantly from non-SCD. Third-party and autologous (SCD) T cell proliferation was suppressed in a dose-dependent manner by all MSCs. SCD MSCs comparably expressed indoleamine-2,3-dioxygenase, which based on transwell and blocking experiments appeared to be the dominant immunomodulatory pathway. The expression of key genes involved in hematopoietic stem cell (HSC)-MSC interactions was minimally altered between SCD and non-SCD MSCs. Expression was, however, altered by IFN-γ stimulation, particularly CXCL14, CXCL26, CX3CL1, CKITL, and JAG1, indicating the potential to augment MSC expression by cytokine stimulation. These data demonstrate the feasibility of expanding BM-derived MSCs from SCD patients that phenotypically and functionally do not differ per International Society of Cell Therapy essential criteria from non-SCD MSCs, supporting initial evaluation (primarily for safety) of autologous MSCs to enhance haploidentical HSC engraftment in SCD.
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia. Electronic address: estenge@emory.edu.
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Stenger
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Raghavan
authors.initials: R
authors.lastname: Chinnadurai
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Shala
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Marco
authors.initials: M
authors.lastname: Garcia
authors.affiliation: School of Biology, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Dalia
authors.initials: D
authors.lastname: Arafat
authors.affiliation: School of Biology, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Greg
authors.initials: G
authors.lastname: Gibson
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.
authors.forename: Lakshmanan
authors.initials: L
authors.lastname: Krishnamurti
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
mesh_terms: D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000473:pathology / Q000628:therapy*; D002450:Cell Communication / Q000235:genetics; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D064368:Healthy Volunteers; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D016130:Immunophenotyping; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D014182:Transplantation, Autologous / Q000379:methods; D055815:Young Adult
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase
keywords: Hematopoiesis; Hematopoietic stem cell transplantation; Mesenchymal stromal cells; Sickle cell disease