title: Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation.
abstract: In the last decade there has been a rapid expansion in clinical trials using mesenchymal stromal cells (MSCs) from a variety of tissues. However, despite similarities in morphology, immunophenotype, and differentiation behavior in vitro, MSCs sourced from distinct tissues do not necessarily have equivalent biological properties. We performed a genome-wide methylation, transcription, and in vivo evaluation of MSCs from human bone marrow (BM), white adipose tissue, umbilical cord, and skin cultured in humanized media. Surprisingly, only BM-derived MSCs spontaneously formed a BM cavity through a vascularized cartilage intermediate in vivo that was progressively replaced by hematopoietic tissue and bone. Only BM-derived MSCs exhibited a chondrogenic transcriptional program with hypomethylation and increased expression of RUNX3, RUNX2, BGLAP, MMP13, and ITGA10 consistent with a latent and primed skeletal developmental potential. The humanized MSC-derived microenvironment permitted homing and maintenance of long-term murine SLAM(+) hematopoietic stem cells (HSCs), as well as human CD34(+)/CD38(-)/CD90(+)/CD45RA(+) HSCs after cord blood transplantation. These studies underscore the profound differences in developmental potential between MSC sources independent of donor age, with implications for their clinical use. We also demonstrate a tractable human niche model for studying homing and engraftment of human hematopoietic cells in normal and neoplastic states.
authors.affiliation: Stem Cell Research Unit and Division of Hematology and Stem Cell Transplantation, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford University, Stanford, CA;
authors.forename: Andreas
authors.initials: A
authors.lastname: Reinisch
authors.affiliation: Stem Cell Research Unit and Division of Hematology and Stem Cell Transplantation, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, Graz, Austria;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Etchart
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford University, Stanford, CA;
authors.forename: Daniel
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Stem Cell Research Unit and Division of Hematology and Stem Cell Transplantation, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Hofmann
authors.affiliation: Stem Cell Research Unit and Division of Hematology and Stem Cell Transplantation, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
authors.forename: Margareta
authors.initials: M
authors.lastname: Fruehwirth
authors.affiliation: Department of Computer Science, and.
authors.forename: Subarna
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, CA;
authors.forename: Charles K
authors.initials: CK
authors.lastname: Chan
authors.affiliation: Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, CA;
authors.forename: Kshemendra
authors.initials: K
authors.lastname: Senarath-Yapa
authors.affiliation: Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, CA;
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Seo
authors.affiliation: Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, CA;
authors.forename: Taylor
authors.initials: T
authors.lastname: Wearda
authors.affiliation: University Medical Center, Third Department of Medicine, Johannes Gutenberg-University, Mainz, Germany;
authors.forename: Udo F
authors.initials: UF
authors.lastname: Hartwig
authors.affiliation: Institute of Pathology and.
authors.forename: Christine
authors.initials: C
authors.lastname: Beham-Schmid
authors.affiliation: Center for Medical Research, Medical University of Graz, Graz, Austria;
authors.forename: Slave
authors.initials: S
authors.lastname: Trajanoski
authors.affiliation: Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, Rheinisch-Westfälische Technische Hochschule Aachen University Medical School, Aachen, Germany;
authors.forename: Qiong
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, Rheinisch-Westfälische Technische Hochschule Aachen University Medical School, Aachen, Germany;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wagner
authors.affiliation: Department of Diagnostic and Interventional Radiology, University Medical Center, Goettingen, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Dullin
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Goettingen, Germany; Department of Hematology and Oncology, University Medical Center Goettingen, Goettingen, Germany;
authors.forename: Frauke
authors.initials: F
authors.lastname: Alves
authors.affiliation: Departments of Stem Cell Transplantation & Cellular Therapy, Molecular Hematology & Therapy, and Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford University, Stanford, CA; Departments of Pathology and Developmental Biology, Stanford School of Medicine, Stanford University, Stanford, CA;
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.affiliation: Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, CA;
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
authors.affiliation: Stem Cell Research Unit and Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, Graz, Austria; Department of Blood Group Serology and Transfusion Medicine, Paracelsus Medical University, Salzburg, Austria;
authors.forename: Katharina
authors.initials: K
authors.lastname: Schallmoser
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford University, Stanford, CA; Department of Medicine, Division of Hematology, Stanford School of Medicine, Stanford University, Stanford, CA; and.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
authors.affiliation: Stem Cell Research Unit and Division of Hematology and Stem Cell Transplantation, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Institute for Experimental and Clinical Cell Therapy, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Dirk
authors.initials: D
authors.lastname: Strunk
mesh_terms: D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D020219:Chondrogenesis / Q000502:physiology; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D010012:Osteogenesis / Q000502:physiology; D055153:Stem Cell Niche