title: Heterogeneous Niche Activity of Ex-Vivo Expanded MSCs as Factor for Variable Outcomes in Hematopoietic Recovery.
abstract: Ex-vivo expanded mesenchymal stromal cells (MSCs) are increasingly used for paracrine support of hematopoietic stem cell (HSC) regeneration, but inconsistent outcomes have hindered ongoing clinical trials. Here, we show that significant heterogeneity in the niche activity of MSCs is created during their culture in various serum-supplemented media. The MSCs cultured under stimulatory or non-stimulatory culture conditions exhibited differences in colony forming unit-fibroblast contents, expression levels of cross-talk molecules (Jagged-1 and CXCL-12) and their support for HSC self-renewal. Accordingly, the enhancing effects of MSCs on hematopoietic engraftment were only visible when HSCs were co-transplanted with MSCs under stimulatory conditions. Of note, these differences in MSCs and their effects on HSCs were readily reversed by switching the cultures, indicating that the difference in niche activity can be caused by distinct functional state, rather than by clonal heterogeneity. Supporting the findings, transcriptomic analysis showed distinct upstream signaling pathways such as inhibition of P53 and activation of ER-stress response gene ATF4 for MSCs under stimulatory conditions. Taken together, our study shows that the niche activity of MSCs can vary rapidly by the extrinsic cues during culture causing variable outcomes in hematopoietic recoveries, and point to the possibility that MSCs can be pre-screened for more predictable efficacy in various cell therapy trials.
authors.affiliation: Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Ho-Sun
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Choi
authors.affiliation: Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Chu
authors.affiliation: Department of Biological Science, Dong-A university, Busan, Republic of Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Leem
authors.affiliation: Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Il-Hoan
authors.initials: IH
authors.lastname: Oh
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods*; D054377:Chemokine CXCL12 / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D000072100:Jagged-1 Protein / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D019899:Paracrine Communication / Q000187:drug effects; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects; D055153:Stem Cell Niche
chemical_list: D054377:Chemokine CXCL12; D000072100:Jagged-1 Protein