Developmental Regulated Cell Death Programs Account for Colony Elimination and Unstable Mixed-Chimerism in B. Schlosseri: Implications for Allogeneic Graft Survival

Daniel M. Corey, Mark Kowarsky, Benyamin Rosental, Katherine Ishizuka, Karla Palmeri, Rahul Sinha, Ayelet Voskoboynik, Stephen Quake, Irving Weissman

Research output: Contribution to journalMeeting Abstract

Abstract

To understand mechanisms fundamental to the maintenance of allogeneic mixed-chimerism we conducted a detailed anatomic and transcriptional analysis of B. schlosseri natural chimeras, a colonial protochordate that undergoes a genetically controlled natural transplantation reaction to create natural parabionts. The life history of B. schlosseri offers a unique platform to study persistence of allogeneic cells in a host. Fusion of blood vessels between two histocompatible, but genetically distinct organisms or colonies creates natural chimeras. Natural history studies among fused-colonies show partners rarely exist as stable chimeras. One chimeric partner is often eliminated in a process of allogeneic resorption. Here we show elimination of chimeric partners involves co-opting programmed cell death and cell-removal pathways during the developmental-regulated ‘takeover’ period of colony life. B. schlosseri colonies reproduce by a process of asexual budding in a highly coordinated weekly blastogenic cycle that ends in a massive apoptotic and phagocytic event of parental individuals. We identified 4266 genes from global RNA-seq expression profiling that changed at least four-fold (FDR < 0.05) shared by both blastogenic takeover and chimeric fusion-partner resorption. Among these, 275 genes increased by expression of at least 50 fold. These include an IL-17 family member (IL-17C), the phagocytic receptors (MerTK, AXL), a programmed cell removal factor (MFGE-8), vascular adhesion molecules (SELP, SELE, Tie1), complement factors (C3, MASP1, MASP2), coagulation factors (F2, F8, KLK3, KLKB1), TNF associated proteins (TRAF3, TRAF4), and matrix metalloproteinases (MMP9, MMP14, MMP16). Among the major pathways identified in chimeric partner elimination are key innate immune signaling processes under the GO terms for “blood coagulation”, “cell death”, “proteolysis,” and “cellular adhesion.” Major characteristics of the transcriptional and cellular programs that underlie chimeric fusion-partner resorption and their implications for development of new strategies to promote allogeneic graft survival in hematopoietic cell transplantation [HCT] will be presented.
Original languageEnglish GB
Pages (from-to)S310-S310
JournalBiology of Blood and Marrow Transplantation
Volume22
Issue number3
DOIs
StatePublished - Mar 2016
Externally publishedYes

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