TY - JOUR
T1 - Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation
AU - Reinisch, Andreas
AU - Etchart, Nathalie
AU - Thomas, Daniel
AU - Hofmann, Nicole A.
AU - Fruehwirth, Margareta
AU - Sinha, Subarna
AU - Chan, Charles K.
AU - Senarath-Yapa, Kshemendra
AU - Seo, Eun Young
AU - Wearda, Taylor
AU - Hartwig, Udo F.
AU - Beham-Schmid, Christine
AU - Trajanoski, Slave
AU - Lin, Qiong
AU - Wagner, Wolfgang
AU - Dullin, Christian
AU - Alves, Frauke
AU - Andreeff, Michael
AU - Weissman, Irving L.
AU - Longaker, Michael T.
AU - Schallmoser, Katharina
AU - Majeti, Ravindra
AU - Strunk, Dirk
N1 - Publisher Copyright:
© 2015 by The American Society of Hematology
PY - 2015/8/8
Y1 - 2015/8/8
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2014-04-572255
DO - 10.1182/blood-2014-04-572255
M3 - Article
C2 - 25406351
AN - SCOPUS:84920973388
SN - 0006-4971
VL - 125
SP - 249
EP - 260
JO - Blood
JF - Blood
IS - 2
ER -