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

• Published in: Blood Vol. 125; no. 2; pp. 249 - 260
• Main Authors: Reinisch, Andreas, Etchart, Nathalie, Thomas, Daniel, Hofmann, Nicole A., Fruehwirth, Margareta, Sinha, Subarna, Chan, Charles K., Senarath-Yapa, Kshemendra, Seo, Eun-Young, Wearda, Taylor, Hartwig, Udo F., Beham-Schmid, Christine, Trajanoski, Slave, Lin, Qiong, Wagner, Wolfgang, Dullin, Christian, Alves, Frauke, Andreeff, Michael, Weissman, Irving L., Longaker, Michael T., Schallmoser, Katharina, Majeti, Ravindra, Strunk, Dirk
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.01.2015; American Society of Hematology
• Subjects: Blotting, Western; Bone Marrow Cells - cytology; Cell Differentiation - physiology; Cell Lineage; Chondrogenesis - physiology; Epigenesis, Genetic; Flow Cytometry; Hematopoiesis and Stem Cells; Hematopoietic Stem Cells - cytology; Humans; Mesenchymal Stem Cells - cytology; Osteogenesis - physiology; Stem Cell Niche
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2014-04-572255

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. •Epigenetics and in vivo behavior can distinguish MSCs from different sources.•BM-derived MSCs form a hematopoietic niche via a vascularized cartilage intermediate.