Dynamic compaction of human mesenchymal stem/precursor cells into spheres self-activates caspase-dependent il1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1)

Thomas J. Bartosh, Joni H. Ylöstalo, Nikolay Bazhanov, Jessica Kuhlman, Darwin J. Prockop

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Human mesenchymal stem/precursor cells (MSC) are similar to some other stem/progenitor cells in that they compact into spheres when cultured in hanging drops or on nonadherent surfaces. Assembly of MSC into spheres alters many of their properties, including enhanced secretion of factors that mediate inflammatory and immune responses. Here we demonstrated that MSC spontaneously aggregated into sphere-like structures after injection into a subcutaneous air pouch or the peritoneum of mice. The structures were similar to MSC spheres formed in cultures demonstrated by the increased expression of genes for inflammation-modulating factors TSG6, STC1, and COX2, a key enzyme in production of PGE2. To identify the signaling pathways involved, hanging drop cultures were used to follow the time-dependent changes in the cells as they compacted into spheres. Among the genes upregu-lated were genes for the stress-activated signaling pathway for IL1a/b, and the contact-dependent signaling pathway for Notch. An inhibitor of caspases reduced the upregulation of IL1A/B expression, and inhibitors of IL1 signaling decreased production of PGE2, TSG6, and STC1. Also, inhibition of IL1A/B expression and secretion of PGE2 negated the anti-inflammatory effects of MSC spheres on stimulated macrophages. Experiments with c-secretase inhibitors suggested that Notch signaling was also required for production of PGE2 but not TSG6 or STC1. The results indicated that assembly of MSC into spheres triggers caspase-dependent IL1 signaling and the secretion of modulators of inflammation and immunity. Similar aggregation in vivo may account for some of the effects observed with administration of the cells in animal models.

Original languageEnglish (US)
Pages (from-to)2443-2456
Number of pages14
JournalStem Cells
Volume31
Issue number11
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Caspases
Mesenchymal Stromal Cells
Dinoprostone
Immunity
Inflammation
Stem Cells
Amyloid Precursor Protein Secretases
Caspase Inhibitors
Peritoneum
Genes
Anti-Inflammatory Agents
Up-Regulation
Animal Models
Macrophages
Air
Gene Expression
Injections
Enzymes

Keywords

  • Caspase
  • Interleukin 1
  • Mesenchymal stem cell
  • Notch
  • Prostaglandin E2
  • Sphere

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Dynamic compaction of human mesenchymal stem/precursor cells into spheres self-activates caspase-dependent il1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1). / Bartosh, Thomas J.; Ylöstalo, Joni H.; Bazhanov, Nikolay; Kuhlman, Jessica; Prockop, Darwin J.

In: Stem Cells, Vol. 31, No. 11, 2013, p. 2443-2456.

Research output: Contribution to journalArticle

Bartosh, Thomas J. ; Ylöstalo, Joni H. ; Bazhanov, Nikolay ; Kuhlman, Jessica ; Prockop, Darwin J. / Dynamic compaction of human mesenchymal stem/precursor cells into spheres self-activates caspase-dependent il1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1). In: Stem Cells. 2013 ; Vol. 31, No. 11. pp. 2443-2456.
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