PMID- 34193955
OWN - NLM
STAT- MEDLINE
DCOM- 20211108
LR  - 20211108
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 11
IP  - 1
DP  - 2021 Jun 30
TI  - Multipotent adult progenitor cells induce regulatory T cells and promote their 
      suppressive phenotype via TGFbeta and monocyte-dependent mechanisms.
PG  - 13549
LID - 10.1038/s41598-021-93025-x [doi]
LID - 13549
AB  - Dysregulation of the immune system can initiate chronic inflammatory responses 
      that exacerbate disease pathology. Multipotent adult progenitor cells (MAPC 
      cells), an adult adherent bone-marrow derived stromal cell, have been observed to 
      promote the resolution of uncontrolled inflammatory responses in a variety of 
      clinical conditions including acute ischemic stroke, acute myocardial infarction 
      (AMI), graft vs host disease (GvHD), and acute respiratory distress syndrome 
      (ARDS). One of the proposed mechanisms by which MAPC cells modulate immune 
      responses is via the induction of regulatory T cells (Tregs), however, the 
      mechanism(s) involved remains to be fully elucidated. Herein, we demonstrate 
      that, in an in vitro setting, MAPC cells increase Treg frequencies by promoting 
      Treg proliferation and CD4(+) T cell differentiation into Tregs. Moreover, MAPC 
      cell-induced Tregs (miTregs) have a more suppressive phenotype characterized by 
      increased expression of CTLA-4, HLA-DR, and PD-L1 and T cell suppression 
      capacity. MAPC cells also promoted Treg activation by inducing CD45RA(+) 
      CD45RO(+) transitional Tregs. Additionally, we identify transforming growth 
      factor beta (TGFbeta) as an essential factor for Treg induction secreted by MAPC 
      cells. Furthermore, inhibition of indoleamine 2, 3-dioxygenase (IDO) resulted in 
      decreased Treg induction by MAPC cells demonstrating IDO involvement. Our studies 
      also show that CD14(+) monocytes play a critical role in Treg induction by MAPC 
      cells. Our study describes MAPC cell dependent Treg phenotypic changes and 
      provides evidence of potential mechanisms by which MAPC cells promote Treg 
      differentiation.
FAU - Valentin-Torres, Alice
AU  - Valentin-Torres A
AD  - Athersys, Inc. Cleveland, 3201 Carnegie Ave., Cleveland, OH, 44115, USA. 
      Avalentin-torres@Athersys.com.
FAU - Day, Cora
AU  - Day C
AD  - Athersys, Inc. Cleveland, 3201 Carnegie Ave., Cleveland, OH, 44115, USA.
FAU - Taggart, Jennifer M
AU  - Taggart JM
AD  - Athersys, Inc. Cleveland, 3201 Carnegie Ave., Cleveland, OH, 44115, USA.
FAU - Williams, Nicholas
AU  - Williams N
AD  - Athersys, Inc. Cleveland, 3201 Carnegie Ave., Cleveland, OH, 44115, USA.
FAU - Stubblefield, Samantha R
AU  - Stubblefield SR
AD  - Athersys, Inc. Cleveland, 3201 Carnegie Ave., Cleveland, OH, 44115, USA.
FAU - Roobrouck, Valerie D
AU  - Roobrouck VD
AD  - ReGenesys BV, Leuven, Belgium.
FAU - Beyens, Jelle
AU  - Beyens J
AD  - ReGenesys BV, Leuven, Belgium.
FAU - Ting, Anthony E
AU  - Ting AE
AD  - Athersys, Inc. Cleveland, 3201 Carnegie Ave., Cleveland, OH, 44115, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210630
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
MH  - Adult Stem Cells/*immunology
MH  - Humans
MH  - *Immune Tolerance
MH  - Monocytes/*immunology
MH  - Multipotent Stem Cells/*immunology
MH  - T-Lymphocytes, Regulatory/*immunology
MH  - Transforming Growth Factor beta/*immunology
PMC - PMC8245558
COIS- Alice Valentin-Torres, Cora Day, Jennifer M. Taggart, and Anthony E. Ting are 
      employees of Athersys, Inc. and are shareholders of Athersys, Inc. Valerie D. 
      Roobrouck and Jelle Beyens are employees of ReGenesys BV and are shareholders of 
      Athersys, Inc. Nicholas Williams and Samantha R. Stubblefield were employees of 
      Athersys, Inc. during their contribution to the work submitted herein, but are no 
      longer at Athersys, Inc.; however, they hold shares at Athersys, Inc.
EDAT- 2021/07/02 06:00
MHDA- 2021/11/09 06:00
PMCR- 2021/06/30
CRDT- 2021/07/01 06:46
PHST- 2020/12/10 00:00 [received]
PHST- 2021/06/17 00:00 [accepted]
PHST- 2021/07/01 06:46 [entrez]
PHST- 2021/07/02 06:00 [pubmed]
PHST- 2021/11/09 06:00 [medline]
PHST- 2021/06/30 00:00 [pmc-release]
AID - 10.1038/s41598-021-93025-x [pii]
AID - 93025 [pii]
AID - 10.1038/s41598-021-93025-x [doi]
PST - epublish
SO  - Sci Rep. 2021 Jun 30;11(1):13549. doi: 10.1038/s41598-021-93025-x.