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

Andreas Reinisch, Nathalie Etchart, Daniel Thomas, Nicole A. Hofmann, Margareta Fruehwirth, Subarna Sinha, Charles K. Chan, Kshemendra Senarath-Yapa, Eun Young Seo, Taylor Wearda, Udo F. Hartwig, Christine Beham-Schmid, Slave Trajanoski, Qiong Lin, Wolfgang Wagner, Christian Dullin, Frauke Alves, Michael Andreeff, Irving L. Weissman, Michael T. LongakerKatharina Schallmoser, Ravindra Majeti, Dirk Strunk

Research output: Contribution to journalArticle

110 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)249-260
Number of pages12
JournalBlood
Volume125
Issue number2
DOIs
Publication statusPublished - 8 Aug 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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