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Blood. 2015 Jan 8;125(2):249-60. doi: 10.1182/blood-2014-04-572255. Epub 2014 Nov 18.

Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation.

Author information

1
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;
2
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;
3
Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford University, Stanford, CA;
4
Stem Cell Research Unit and Division of Hematology and Stem Cell Transplantation, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
5
Department of Computer Science, and.
6
Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, CA;
7
University Medical Center, Third Department of Medicine, Johannes Gutenberg-University, Mainz, Germany;
8
Institute of Pathology and.
9
Center for Medical Research, Medical University of Graz, Graz, Austria;
10
Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, Rheinisch-Westfälische Technische Hochschule Aachen University Medical School, Aachen, Germany;
11
Department of Diagnostic and Interventional Radiology, University Medical Center, Goettingen, Germany;
12
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;
13
Departments of Stem Cell Transplantation & Cellular Therapy, Molecular Hematology & Therapy, and Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
14
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;
15
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;
16
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.
17
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.

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.

PMID:
25406351
PMCID:
PMC4287636
DOI:
10.1182/blood-2014-04-572255
[Indexed for MEDLINE]
Free PMC Article

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