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mesenchymal stem cells

WHAT ARE MESENCHYMAL STEM CELLS (MSC) ?. First isolated by Friedenstein et al in 1974Fibroblastoid cells - spindle-shapedAdherent to tissue culture glass or plasticHigh growth potential. WHY ARE MSC INTERESTING ?. Rat MSC genetically tagged are microinjected into a mouse blastocyteBlastocyte reimplanted into another ratBlastocyte allowed to develop into baby rat -> sacrificedGene tags are found in many of the baby rat tissues tested ->Embryonic stem cells?.

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mesenchymal stem cells

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    1. MESENCHYMAL STEM CELLS SK Cheong, Dept of Diagnostic Laboratory Services, Hospital UKM

    3. WHY ARE MSC INTERESTING ? Rat MSC genetically tagged are microinjected into a mouse blastocyte Blastocyte reimplanted into another rat Blastocyte allowed to develop into baby rat -> sacrificed Gene tags are found in many of the baby rat tissues tested ->Embryonic stem cells?

    5. In vitro MSC growth pattern-doubling time 33hr

    6. HOW TO ISOLATE MSC? Sources: BM, periosteum, synovium, fat, cord blood, peripheral blood, foetal liver and lung Adherent to culture bottle; haemopoietic stem cells do not Easily subcultured

    7. HOW TO IDENTIFY MSC? Morphology Adherent to glass or plastic Surface markers: SH2, SH3, SH4, STRO-1, ICAM-2, NCAM, integrins, PDGF, IL-IR Capable to be induced in vitro to differentiate into osteoblasts, chondrocytes, and adipocytes

    9. APPEALING CHARACTERSITICS Pluripotent - self renewal and wide differentiation into multiple lineages Can home to the bone marrow Can be incorporated direct into other tissues Low immunogenicity and suppress alloreactive T cell response (transplanted allogenic MSC are not rejected)

    10. TRANSDIFFERENTIATION MSC – mesodermal origin Can differentiate into cells of endodermal and ectoderml origins Neurons, hepatocytes, islet cells, skin (fusion controversy)

    12. REPORTED USE OF MSC

    13. ADENOSINE DEAMINASE DEFICIENCY Gerson et al 1997 implanted subcut MSC graft transduced with a functional adenosine deaminase gene

    14. FABRY’S DISEASE X-linked genetic disorder - deficiency of lysosomal enzyme alpha-galactosidase Using patient’s own MSC Transduced with a functional galactosidase gene Return MSC to the patient Correction of deficiency (Osiris, 2000)

    15. OSTEOGENESIS IMPERFECTA Horwitz et al 1999 reported 3 children transplanted with allogeneic MSC from HLA-compatible siblings New lamellar bone formation, improved osteogenesis with fewer fractures Engrafted MSC were shown to differentiate into osteoblasts

    17. REDUCE GRAFT-VS-HOST RESPONSE MSC induce T cell apoptosis Clinical trial conducted (Osiris, Italy & USA) Results showed reduced or milder acute and chronic GVH responses (Frassoni et al 2002,2003)

    18. Immediate POTENTIAL APPLICATION

    19. SINGLE GENE DISORDERS 1.Hemophilias 2.In-born errors of metabolism Transduced MSC with a functional gene Reinfusion of autologous engineered MSC May cure these disorders Osiris Therapeutic Inc. 2001

    21. ANAEMIA CORRECTION Erythropoietin shown to be useful in chronic renal failure and anemia of cancers MSC transduced with erythropoietin gene (Lim & Cheong 2003) May be as good as external injection

    22. INSULIN FOR TYPE I DIABETES MELLITUS Insulin deficiency Can be corrected with islet cell transplant MSC ->brand new autologous islet cells MSC -> transduced with gene responsible for insulin production Allogeneic transdued MSC also feasible

    23. REPARATIVE MEDICINE Since MSC are pluripotent and capable of be induced to differentiate into different type of cells Exploited to replace diseased cells or tissues ? Heart cells for infarcted myocardium ? Neurons for Parkinson’s disease ? Meniscus regenaration and replacement

    25. STEM CELL Research Group in UKM Clinical Haematology & Stem Cell Transplant Molecular Haematology Flow Cytometry Cell Culture Cheong Soon Keng S Fadilah A Wahid Leong Chooi Fun Ainoon Othman Wong Fei Liang Noor Hamidah Hussin K Sivagengei Maha Abdullah (UPM) Lim Moon Nian (IMR)

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