NOD2 Activation promotes anti-inflammatory activity of human Umbilical cord blood MSCs against Inflammatory bowel disease
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1 NOD2 Activation promotes anti-inflammatory activity of human Umbilical cord blood MSCs against Inflammatory bowel disease Prof. Kyung-Sun Kang, DVM, PhD. Adult Stem Cell Research Center Seoul National University, Seoul Korea
2 Acknowledgement Collaborators; Byung-Chul Lee Hyung-Sick Kim Tae-Hoon Shin Gabriel Núñez, University of Michigan, USA Jong-Hwan Park, Konyang University, Korea 2
3 Inflammatory Bowel Disease; Ulcerative Colitis & Crohn s Disease TNBS: Trinitrobenzene sulfonic acid DSS: Dextran Sulfate Sodium
4 Crohn's Disease Marked by Dramatic Changes in Gut Bacteria 12 March :00 pm thumb_article_l/public/sn-crohns.jpg The research, which involved 668 children, shows that numbers of some beneficial bacteria in the gut decrease in Crohn's patients, while the number of potentially harmful bacteria increases. 4
5 Pattern recognition receptors? NOD2 receptor and it s mutation site - Toll-like receptor :13 - NOD-like receptor : 23 - IBD & NOD2 NOD2 receptor in Intestinal homeostasis
6 NOD2; Nucleotide-binding oligomerization domain 2 1. a member of the cytosolic Nod-like receptor (NLR) family 2. consists of two N-terminal caspase-recruiting domains (CARDs), a central nucleotide binding oligomerization domain (NOD), and a C-terminal leucine rich repeat (LRR) domain for recognition of microbial molecules. 3. NOD2 senses muramyl dipeptide (MDP), a small molecule derived from the peptidoglycan of bacterial cell wall, 4. activates the serine-threonine kinase RICK (RIP-like interacting CLARP kinase) [also known as receptorinteracting protein 2 (RIP2)] via a CARD-CARD interaction (Chen et al., 2009; Inohara et al., 2003).
7 NOD2 and Crohn s Disease
8 Proposed Mechanisms of NOD2 function in intestinal homeostasis NOD2 in transplanted cells (MSCs)??
9 The youngest, most primitive MS Cs NOD2 is functionally expressed in human cord blood stem cells not in the bone marrow stem cells BM- MSC UCB- MSC UCB AD BM NOD2 GAPDH ICM Fertilized egg Blastocyst prenatal postnatal hucb-stem cells had/hbm-mscs
10
11 Colitis induction and Trafficking of infused hucb-mscs 3% DSS ad libitum 3% DSS TNBS MSC Injection days DSS withdrawal Sacrifice No Cells CFSE UCB CFSE UCB Negative hucb-mscs hucb-mdp
12 NOD2-activated hucb-mscs enhanced protective effects against chemically-induced colitis
13 (-) PBS UCB UCB + MDP UCB-siNOD2 + MDP Kim et. al., 2013, Gastroenterology 13
14 NOD2-activated hucb-mscs reduce colonic inflammation in colitis Kim st. al 2013, Gastroenterology
15 15
16 NOD2-activated hucb-mscs increased the colonic infiltration of Foxp3 + cells A (-) PBS UCB UCB + MDP UCB-siNOD2+MDP Foxp3 B (-) PBS MSC MSC +MDP MSC -sinod2 +MDP C Foxp3 GAPDH Kim et. al., 2013, Gastroenterlogy
17 MDP-induced PGE 2 is responsible for MNCs suppression by hucb-mscs COX-2 GAPDH (-) Pam 3 LPS T-DAP MDP Kim et. al., 2013, Gastroenterology
18 Immunosuppressive effect of hucb-mscs through NOD2-Rip2 dependent pathway COX-2 GAPDH Kim et. al., 2013, Gastroenterology
19 COX-2 GAPDH 19
20 MDP-induced PGE 2 via NOD2-RIP2 signaling increased IL-10 production and regulatory T cell population in hmncs Kim et. al., 2013, Gastroenterology
21 Multiple Action Mechanisms of human UCB-MSCs in Colitis microflora Colitis T cell Foxp3 - CD4 + NOD2 IL6 APC T cell Stem cells PGE2 MNC IFNg, TNFa IL-10 Th1/Th17 IL17 IL22 Colitis +UCB-MSCs
22 Phase 1/2a Clinical Trial for Crohn s Disease BLA PHASE 3 PHASE 2b PHASE 1&2a IND IND approval (by MFDS) Early Market Advance Plan to obtain Conditional Approval as an orphan drug once phase 2b clinical trial is completed. 22
23 If I have seen further, it is only by standing on the shoulders of giants. -Isaac Newton Thank you!!
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