Solution-phase crosstalk and regulatory interactions between multipotent adult progenitor cells and peripheral blood mononuclear cells

Gregory G. Burrows, Wouter Van’T Hof, Ashok P. Reddy, Phillip Wilmarth, Larry David, Amy Raber, Annelies Bogaerts, Lien Timmerman, Jef Pinxteren, Valerie D. Roobrouck, Robert J. Deans, Richard Maziarz

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Multipotent adult progenitor cells (MAPCs) are adult adherent stromal stem cells currently being assessedin clinical trials foracutegraft versus host disease with demonstrated im munomodulatory capabilities and the potential to ameliorate detrimental autoimmune and inflammation-related processes. Anti-CD3/anti-CD28(3/28) activation of T cells within the peripheral blood mononuclear cell (PBMC) compartmentwas performed in the presence or absence of MAPCs. Liquid chromatography-coupled tandem mass spectrometry was used to characterize the differential secretion of proteins, and transcriptional profiling was used to monitorm RNA expression changes in both cell populations. Overall, 239 secreted and/or ectodomain-shed proteins were detected in the secretomes of PBMCs and MAPCs. In addition, 3/28 activation of PBMCs induced differential expression of 2,925 genes, and 22% of these transcripts were differentially expressed on exposure to MAPCs in Transwell. MAPCs exposed to 3/28-activated PBMCs showed differential expression of 1,247MAPC genes. Crosstalk was demonstrated by reciprocal transcriptional regulation. Secretome proteins and transcriptional signatures were used to predict molecular activities by which MAPCs could dampen local and systemic inflammatory responses. These data support the hypothesis that MAPCs block PBMC proliferation via cell cycle arrest coupled to metabolic stress in the form of tryptophan depletion, resulting in GCN2 kinase activation, downstream signaling, and inhibition of cyclin D1 translation. These data also provide a plausible explanation for the immune privilege reported with administration of donor MAPCs. Although most components of the major histocompatibility complex class II antigen presentation pathway were markedly transcriptionally upregulated, cell surface expression of human leukocyte antigen-DR is minimal on MAPCs exposed to 3/28-activated PBMCs.

Original languageEnglish (US)
Pages (from-to)1436-1449
Number of pages14
JournalStem cells translational medicine
Volume4
Issue number12
DOIs
StatePublished - Dec 1 2015

Fingerprint

Blood Cells
Stem Cells
Physiological Stress
Proteins
Cyclin D1
Histocompatibility Antigens Class II
Antigen Presentation
Stromal Cells
HLA Antigens
Tandem Mass Spectrometry
Cell Cycle Checkpoints
Major Histocompatibility Complex
Tryptophan
Liquid Chromatography
Genes
Phosphotransferases
Cell Proliferation
Clinical Trials
RNA
Inflammation

Keywords

  • Anti-CD3/anti-CD28-activated PBMC
  • Cell cycle arrest
  • Immune tolerance
  • MRNA gene array
  • Multipotent adult progenitor cell

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology

Cite this

Solution-phase crosstalk and regulatory interactions between multipotent adult progenitor cells and peripheral blood mononuclear cells. / Burrows, Gregory G.; Hof, Wouter Van’T; Reddy, Ashok P.; Wilmarth, Phillip; David, Larry; Raber, Amy; Bogaerts, Annelies; Timmerman, Lien; Pinxteren, Jef; Roobrouck, Valerie D.; Deans, Robert J.; Maziarz, Richard.

In: Stem cells translational medicine, Vol. 4, No. 12, 01.12.2015, p. 1436-1449.

Research output: Contribution to journalArticle

Burrows, Gregory G. ; Hof, Wouter Van’T ; Reddy, Ashok P. ; Wilmarth, Phillip ; David, Larry ; Raber, Amy ; Bogaerts, Annelies ; Timmerman, Lien ; Pinxteren, Jef ; Roobrouck, Valerie D. ; Deans, Robert J. ; Maziarz, Richard. / Solution-phase crosstalk and regulatory interactions between multipotent adult progenitor cells and peripheral blood mononuclear cells. In: Stem cells translational medicine. 2015 ; Vol. 4, No. 12. pp. 1436-1449.
@article{2cefde156fe242419ec41f6551066bf3,
title = "Solution-phase crosstalk and regulatory interactions between multipotent adult progenitor cells and peripheral blood mononuclear cells",
abstract = "Multipotent adult progenitor cells (MAPCs) are adult adherent stromal stem cells currently being assessedin clinical trials foracutegraft versus host disease with demonstrated im munomodulatory capabilities and the potential to ameliorate detrimental autoimmune and inflammation-related processes. Anti-CD3/anti-CD28(3/28) activation of T cells within the peripheral blood mononuclear cell (PBMC) compartmentwas performed in the presence or absence of MAPCs. Liquid chromatography-coupled tandem mass spectrometry was used to characterize the differential secretion of proteins, and transcriptional profiling was used to monitorm RNA expression changes in both cell populations. Overall, 239 secreted and/or ectodomain-shed proteins were detected in the secretomes of PBMCs and MAPCs. In addition, 3/28 activation of PBMCs induced differential expression of 2,925 genes, and 22{\%} of these transcripts were differentially expressed on exposure to MAPCs in Transwell. MAPCs exposed to 3/28-activated PBMCs showed differential expression of 1,247MAPC genes. Crosstalk was demonstrated by reciprocal transcriptional regulation. Secretome proteins and transcriptional signatures were used to predict molecular activities by which MAPCs could dampen local and systemic inflammatory responses. These data support the hypothesis that MAPCs block PBMC proliferation via cell cycle arrest coupled to metabolic stress in the form of tryptophan depletion, resulting in GCN2 kinase activation, downstream signaling, and inhibition of cyclin D1 translation. These data also provide a plausible explanation for the immune privilege reported with administration of donor MAPCs. Although most components of the major histocompatibility complex class II antigen presentation pathway were markedly transcriptionally upregulated, cell surface expression of human leukocyte antigen-DR is minimal on MAPCs exposed to 3/28-activated PBMCs.",
keywords = "Anti-CD3/anti-CD28-activated PBMC, Cell cycle arrest, Immune tolerance, MRNA gene array, Multipotent adult progenitor cell",
author = "Burrows, {Gregory G.} and Hof, {Wouter Van’T} and Reddy, {Ashok P.} and Phillip Wilmarth and Larry David and Amy Raber and Annelies Bogaerts and Lien Timmerman and Jef Pinxteren and Roobrouck, {Valerie D.} and Deans, {Robert J.} and Richard Maziarz",
year = "2015",
month = "12",
day = "1",
doi = "10.5966/sctm.2014-0225",
language = "English (US)",
volume = "4",
pages = "1436--1449",
journal = "Stem cells translational medicine",
issn = "2157-6564",
publisher = "AlphaMed Press",
number = "12",

}

TY - JOUR

T1 - Solution-phase crosstalk and regulatory interactions between multipotent adult progenitor cells and peripheral blood mononuclear cells

AU - Burrows, Gregory G.

AU - Hof, Wouter Van’T

AU - Reddy, Ashok P.

AU - Wilmarth, Phillip

AU - David, Larry

AU - Raber, Amy

AU - Bogaerts, Annelies

AU - Timmerman, Lien

AU - Pinxteren, Jef

AU - Roobrouck, Valerie D.

AU - Deans, Robert J.

AU - Maziarz, Richard

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Multipotent adult progenitor cells (MAPCs) are adult adherent stromal stem cells currently being assessedin clinical trials foracutegraft versus host disease with demonstrated im munomodulatory capabilities and the potential to ameliorate detrimental autoimmune and inflammation-related processes. Anti-CD3/anti-CD28(3/28) activation of T cells within the peripheral blood mononuclear cell (PBMC) compartmentwas performed in the presence or absence of MAPCs. Liquid chromatography-coupled tandem mass spectrometry was used to characterize the differential secretion of proteins, and transcriptional profiling was used to monitorm RNA expression changes in both cell populations. Overall, 239 secreted and/or ectodomain-shed proteins were detected in the secretomes of PBMCs and MAPCs. In addition, 3/28 activation of PBMCs induced differential expression of 2,925 genes, and 22% of these transcripts were differentially expressed on exposure to MAPCs in Transwell. MAPCs exposed to 3/28-activated PBMCs showed differential expression of 1,247MAPC genes. Crosstalk was demonstrated by reciprocal transcriptional regulation. Secretome proteins and transcriptional signatures were used to predict molecular activities by which MAPCs could dampen local and systemic inflammatory responses. These data support the hypothesis that MAPCs block PBMC proliferation via cell cycle arrest coupled to metabolic stress in the form of tryptophan depletion, resulting in GCN2 kinase activation, downstream signaling, and inhibition of cyclin D1 translation. These data also provide a plausible explanation for the immune privilege reported with administration of donor MAPCs. Although most components of the major histocompatibility complex class II antigen presentation pathway were markedly transcriptionally upregulated, cell surface expression of human leukocyte antigen-DR is minimal on MAPCs exposed to 3/28-activated PBMCs.

AB - Multipotent adult progenitor cells (MAPCs) are adult adherent stromal stem cells currently being assessedin clinical trials foracutegraft versus host disease with demonstrated im munomodulatory capabilities and the potential to ameliorate detrimental autoimmune and inflammation-related processes. Anti-CD3/anti-CD28(3/28) activation of T cells within the peripheral blood mononuclear cell (PBMC) compartmentwas performed in the presence or absence of MAPCs. Liquid chromatography-coupled tandem mass spectrometry was used to characterize the differential secretion of proteins, and transcriptional profiling was used to monitorm RNA expression changes in both cell populations. Overall, 239 secreted and/or ectodomain-shed proteins were detected in the secretomes of PBMCs and MAPCs. In addition, 3/28 activation of PBMCs induced differential expression of 2,925 genes, and 22% of these transcripts were differentially expressed on exposure to MAPCs in Transwell. MAPCs exposed to 3/28-activated PBMCs showed differential expression of 1,247MAPC genes. Crosstalk was demonstrated by reciprocal transcriptional regulation. Secretome proteins and transcriptional signatures were used to predict molecular activities by which MAPCs could dampen local and systemic inflammatory responses. These data support the hypothesis that MAPCs block PBMC proliferation via cell cycle arrest coupled to metabolic stress in the form of tryptophan depletion, resulting in GCN2 kinase activation, downstream signaling, and inhibition of cyclin D1 translation. These data also provide a plausible explanation for the immune privilege reported with administration of donor MAPCs. Although most components of the major histocompatibility complex class II antigen presentation pathway were markedly transcriptionally upregulated, cell surface expression of human leukocyte antigen-DR is minimal on MAPCs exposed to 3/28-activated PBMCs.

KW - Anti-CD3/anti-CD28-activated PBMC

KW - Cell cycle arrest

KW - Immune tolerance

KW - MRNA gene array

KW - Multipotent adult progenitor cell

UR - http://www.scopus.com/inward/record.url?scp=84949650074&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949650074&partnerID=8YFLogxK

U2 - 10.5966/sctm.2014-0225

DO - 10.5966/sctm.2014-0225

M3 - Article

VL - 4

SP - 1436

EP - 1449

JO - Stem cells translational medicine

JF - Stem cells translational medicine

SN - 2157-6564

IS - 12

ER -