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Sai Kiang LIM
Topical MSC exosome drug for psoriasis Institute of Molecular & Cell Biology, Singapore |
Abstract
Mesenchymal stem cells (MSCs) are the most clinically trialed regenerative stem cells. Many of the reported MSC-associated therapeutic efficacies could now be attributed to secreted small extracellular vesicles such as exosomes in their secretion. In 2008, my group was the first to report that the therapeutic active agent in MSC secretion was a large >1000 kD factor. We isolated this factor and identified the factor as exosomes in 2010. Since 2010, exosomes were found to mediate the therapeutic efficacy of MSCs in many diseases.
Mesenchymal stem/stromal cell (MSC) exosomes are widely known for their potent immunomodulatory properties. Recently, we reported that when topically applied, MSC exosomes could alleviate IL-17, a key disease driver of psoriasis in the skin of a mouse model of imiquimod (IMQ)-induced psoriasis. As topically applied MSC exosomes are confined to the stratum corneum, the targets of MSC exosome immunomodulating activity must reside in the stratum corneum. The psoriatic stratum corneum is known to be rich in two immune components, activated complements and infiltrating neutrophils in Munro microabscesses. To investigate if topically applied MSC exosomes reduce IL-17 through a mechanism involving complements or/and neutrophils, we observed for the first time that IL-17 secretion in neutrophils could be induced by the terminal complement complex C5b9 and this induction was inhibited by MSC exosomes. This inhibition was abolished by a neutralizing antibody against CD59 with a concomitant reduction in C5b9 concentration. Together these observations demonstrated that topically applied MSC exosomes reduce IL-17 secretion in psoriatic skin by inhibiting formation of activated complement complexes through exosomal CD59 and thereby reducing IL-17 secretion by neutrophils
Mesenchymal stem cells (MSCs) are the most clinically trialed regenerative stem cells. Many of the reported MSC-associated therapeutic efficacies could now be attributed to secreted small extracellular vesicles such as exosomes in their secretion. In 2008, my group was the first to report that the therapeutic active agent in MSC secretion was a large >1000 kD factor. We isolated this factor and identified the factor as exosomes in 2010. Since 2010, exosomes were found to mediate the therapeutic efficacy of MSCs in many diseases.
Mesenchymal stem/stromal cell (MSC) exosomes are widely known for their potent immunomodulatory properties. Recently, we reported that when topically applied, MSC exosomes could alleviate IL-17, a key disease driver of psoriasis in the skin of a mouse model of imiquimod (IMQ)-induced psoriasis. As topically applied MSC exosomes are confined to the stratum corneum, the targets of MSC exosome immunomodulating activity must reside in the stratum corneum. The psoriatic stratum corneum is known to be rich in two immune components, activated complements and infiltrating neutrophils in Munro microabscesses. To investigate if topically applied MSC exosomes reduce IL-17 through a mechanism involving complements or/and neutrophils, we observed for the first time that IL-17 secretion in neutrophils could be induced by the terminal complement complex C5b9 and this induction was inhibited by MSC exosomes. This inhibition was abolished by a neutralizing antibody against CD59 with a concomitant reduction in C5b9 concentration. Together these observations demonstrated that topically applied MSC exosomes reduce IL-17 secretion in psoriatic skin by inhibiting formation of activated complement complexes through exosomal CD59 and thereby reducing IL-17 secretion by neutrophils
Bio
Sai-Kiang Lim graduated with a B.Sc (Hons in Biochemistry) from National University of Singapore in 1985 and a PhD (Molecular Biology) from SUNY at Buffalo in 1992. Her PhD thesis was on the metabolism of thalassemic mRNA under the mentorship of Prof Lynne Maquat (Dept. of Human Genetics, Roswell Park Cancer Institute). Based on this work, she was awarded the Most Meritorious Student Research Award by Sigma Xi Society in 1989, NY State Predoctoral Fellowship (1989-91). In 1992, she started postdoctoral training on erythroid differentiation with Prof Frank Constantini (Dept. of Genetics and Development College of Physicians & Surgeons, Columbia University) first as a Cooley’s Anemia Foundation Research Fellow (1992-94) and then as a Leukemia Society of America Special Fellow (1994-96). After postdoctoral training, she led independent research groups at NUMI, NUS (1996-2001), Genome Institute of Singapore (2002-2007) and then Institute of Medical Biology (2007-2020). Her research focus has always been disease-related with emphasis on the elucidation of the underlying molecular and cellular mechanisms in diseases and development of therapies. Presently, her major research interests are in natural and synthetic nano lipid vesicles with specific focus on their synthesis and purification, biochemical and biophysical characterisation, and diagnostic and therapeutic applications. Her two most notable scientific achievements are the discovery of stable mRNA decay intermediates in eukaryotic cells and the discovery of therapeutic MSC exosomes. As of Aug 2019, her patent portfolio consists of 8 families: 71 granted patents and 32 pending applications. She is a key opinion leader in therapeutic EVs. She has founded two start-ups, Paracrine Therapeutics and Vesiderm. She is a founding member of SSCR (founding president), SOCRATES and ISEV. Presently, she is the Co-chair of the ISCT Exosome Committee and member of the ISEV Taskforce on the Use of Unproven Extracellular Vesicle Therapies. She was also the lead organizer of several international workshops on exosomes in Singapore: 1) 2015 ISEV Research Workshop: Application of Therapeutic EVs in Patients, 2) 2018 and 3) 2019 SOCRATES, ISCT, ISEV and ISBT Joint MSC-sEV workshops. She was a member of IOC for ISCT Annual Meeting organising committee, 2018 & 2019, and ISEV Annual Meeting 2019.
Sai-Kiang Lim graduated with a B.Sc (Hons in Biochemistry) from National University of Singapore in 1985 and a PhD (Molecular Biology) from SUNY at Buffalo in 1992. Her PhD thesis was on the metabolism of thalassemic mRNA under the mentorship of Prof Lynne Maquat (Dept. of Human Genetics, Roswell Park Cancer Institute). Based on this work, she was awarded the Most Meritorious Student Research Award by Sigma Xi Society in 1989, NY State Predoctoral Fellowship (1989-91). In 1992, she started postdoctoral training on erythroid differentiation with Prof Frank Constantini (Dept. of Genetics and Development College of Physicians & Surgeons, Columbia University) first as a Cooley’s Anemia Foundation Research Fellow (1992-94) and then as a Leukemia Society of America Special Fellow (1994-96). After postdoctoral training, she led independent research groups at NUMI, NUS (1996-2001), Genome Institute of Singapore (2002-2007) and then Institute of Medical Biology (2007-2020). Her research focus has always been disease-related with emphasis on the elucidation of the underlying molecular and cellular mechanisms in diseases and development of therapies. Presently, her major research interests are in natural and synthetic nano lipid vesicles with specific focus on their synthesis and purification, biochemical and biophysical characterisation, and diagnostic and therapeutic applications. Her two most notable scientific achievements are the discovery of stable mRNA decay intermediates in eukaryotic cells and the discovery of therapeutic MSC exosomes. As of Aug 2019, her patent portfolio consists of 8 families: 71 granted patents and 32 pending applications. She is a key opinion leader in therapeutic EVs. She has founded two start-ups, Paracrine Therapeutics and Vesiderm. She is a founding member of SSCR (founding president), SOCRATES and ISEV. Presently, she is the Co-chair of the ISCT Exosome Committee and member of the ISEV Taskforce on the Use of Unproven Extracellular Vesicle Therapies. She was also the lead organizer of several international workshops on exosomes in Singapore: 1) 2015 ISEV Research Workshop: Application of Therapeutic EVs in Patients, 2) 2018 and 3) 2019 SOCRATES, ISCT, ISEV and ISBT Joint MSC-sEV workshops. She was a member of IOC for ISCT Annual Meeting organising committee, 2018 & 2019, and ISEV Annual Meeting 2019.
Chair
Freda LIM, IHPC, Singapore
Freda LIM, IHPC, Singapore