Dissection of the Human Multipotent Adult Progenitor Cell (MAPC) Secretome by Proteomic Analysis

ABSTRACT: Multipotent adult progenitor cells (MAPC; Multistem®) are adult adherent stromal stem cells currently being assessed in acute GVHD clinical trials with demonstrated immunomodulatory capabilities and the potential to ameliorate detrimental autoimmune and inflammation-related processes. Our previous studies documented that MAPC secrete factors that play a role in regulating T cell activity. Here we expand our studies using a proteomics approach to characterize and quantify MAPC secretome components secreted over 72 hours in vitro under steady-state conditions and in the presence of inflammatory triggers IFN-gamma and LPS, or a tolerogenic CD74 ligand, RTL1000. MAPC differentially respond to each of the tested stimuli, secreting molecules that regulate the biological activity of the extra-cellular matrix (ECM), including proteins that comprise the ECM itself, proteins that regulate its construction/de-construction, and proteins that serve to attach and de-attach growth factors from ECM components for redistribution upon appropriate stimulation. MAPC secrete a wide array of proteases, some detectable in their zymogen forms, as well as protease inhibitors that serve to poise the ECM in a state of repose, ready to respond appropriately to differential exogenenous stimuli consequential to local physical injury to tissue or infiltration by various cell types. MAPC also secrete chemokines and cytokines that could provide molecular guidance cues to various cell types including neutrophils, macrophages and T cells, as well as secrete factors known to be involved in maintenance of a homeostatic environment and regulating such diverse programs as innate immunity, angiogenesis/angiostasis, targeted delivery of growth factors, and the matrix-metalloprotease cascade.