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Mesenchymal Stem/Progenitor cells for Therapeutic and Tissue engineer
ing applications
Yu-Hui Tsai, Ph.D. ( Daniel Tzu-bi Shih)
Grad. Inst. Medical SciencesTaipei Medical University
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Stem/Progenitor CellsStem cells• Self Renew (Proliferation)• Muti-differentiation potential (Plasticity) :
Trans-differentiation, Transformation, De-differentiation
Progenitor cells• Functional Undetermined Tissue-cell Precu
sors.• Muti-differentiation potential (Plasticity)
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Types of Stem Cells
– ES Cells (ESCs) [Derived from Embryo inner mass]
– EG Cells (EGCs) [Derived from Fetus gonad]
– Somatic Tissue Stem /Progenitor Cells [ Isolated from Fetus, Neo-natal and Adult Tissues] (tSC, tS/PC): e.g. Neural SCs, Mesenchymal Stem/Progenitor Cells (MSC, MSCs/MPCs), Hemapoietic Stem/Progenitor Cells (HSC, HSCs/HPCs), and Karotinocytes etc.
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Development of the Human Preimplantation Blastocyst
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Development of Human Embryonic Tissues
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The Niche The Niche Determines The Fate Determines The Fate
of Stem Cellsof Stem CellsEcologic/Epigenetical Microenvironment of Stem Ce
lls
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Tissue Stem Cells (tSCs)
Develop & Maintain within Specific Niche
A. Epidermal---Basal Layer
Hair Folocale & Epidermis--- The bulge (Tcf3)
B. Small Intestine--- The crypt Cells ( Tcf4)
C. Neural Precursors Cells--- Ependymal or the Sub Ventricular Zone Cells (AP)
D. Hematopoietic SCs--- Bone Marrow
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Tissue Maintenance and Repair
• I) Tissue Stem/Progenitor Cells
• II) Environmental Cellular Metrix (ECM)
• III) Associate Stroma Cells
• IV) Cytokines
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Basic Requirements for Tissue Regeneration
*Tissue Stem/Progenitor Cells
*Stromal Cells for MicroEnvironmental Support of the Tissue Survival and Normal Functioning.
*Cytokines (Autokine & Parakines) & Chemokines
*Oxygen Supply: Red Blood Cells and Neovascularization
*Sensory Nuron: nurogenesis.
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Adapted from speech of Dr. Bruce A. Mast, M.D.: The Regulation of Wound Healing. Division of Plastic and Reconstructive Surgery Department of Surgery Univeristy of Florida. (http://www.medinfo.ufl.edu/cme/grounds/mast/index.html).
Wound Healing
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CD34+ HS/PCs Functions:
Hematopoietic Reconstitution
Immunotherapy
Neovasculogenesis, Neurogenesis, &Tissue Regenerations etc.
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Comparative analysis of the similar stem cell populations from various origins
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The Niche of HSCs
Marrow(MSC & ECM)
& Soluble Factors
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Tissue Mesenchymal Stem Cells
▪ Connective tissue / stromal source
EX : Bone marrow /Adipose tissue / Skin / Muscle
▪ Umbilical cord blood
Definition:
Sites :
▪Mesenchymal Multi-lineage differentiation potential▪Cell surface antigens expression : SH2/SH4/CD105
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Bone Marrow Mesenchymal stem cells ( BM-MSCs )
Multipotent differentiation
Interact & Support tissue cells
(mesoderm-derived tissue cell type) : adipocyte / osteoblast / chondrocyte / myoblast / endothelial cell
(Ectoderm) : Neural cells
Hematopoiesis and angiogenesis
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Hypotheses to explain the generation of nonhematopoietic tissues from HSC-enriched populations. Totipotential cells derived from the embryo could persist into adult life and be sequestered in the bone marrow, where they could form a reservoir of precursors from which definitive HSCs could develop. Protocols for the enrichment of HSCs based on their phenotypic and physical properties might also result in the isolation of these totipotent cells, which in turn contribute to skeletal or cardiac muscle or cells of the gastrointestinal tract after various transplantation protocols. Alternatively, precursors whose developmental potential is more limited might also be present in the bone marrow. Finally, a pluripotent HSC (PHSC) may be able to alter its genome and transdifferentiate.
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Stem cells find their niche
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NATURE|VOL 428 |11 MARCH 2004|
Creation of long-lasting blood vessels
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Gene expression profiling of BM-MSCs
Undifferentiated human mesenchymal stem cells reveals mRNAs of multiple cell lineages. Tremain,N.2001 / Woodbury,D.2002 / eshi,B.2003
Multipotent :
Growth factors / Matrix proteins / Cell surface molecules :
BM-MSCs expressed various kinds of growth factors,matrix proteins, and cell surface molecules. Silva,W.A.,Jr2003
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Adipose tissue Mesenchymal stem cells (AD-MSCs)
• Similar to Bone marrow mesenchymal stem cells
CD marker antigens
Multipotent differentiation ▪▪
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A Study on Human Tissue Stem/progenitor cells for Medical Application and Drug Discovery
• Bone Marrow• Placental and
Peripheral Blood• Fat Tissue• Scalp• Amnoitic tissue• Fore Skin• Placenta • Teeth
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Stem Cell Isolation and Processing
a. Hematopoietic Stem Cells (HSCs) and Mesodermal Progenitor Cells (MPCs)
MACS
FACS CD34+ cells (HSCs)MNC CD45-GlyA- cells (MPCs)
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c. Processed Lipoaspirate (PLA)
Adherent cells -PLA
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Cell surface antigens expression
Multi-lineage differentiation abilities
How to distinguish tissue stem cells ?
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Hypothesis: Mesenchymal stem cells in different tissues have their own specific potentials in maintenance of their tissue specific niche
Objective : To understand the tissue MSC specificity for better stem cell therapy applications
Is There Specific Niche for Each Type of Tissue Stem/Progenitor Cells in Human?
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By Combining Cellular and Molecular Characterizations of MSCs derived from
Different Tissues in Human, ….
How Specific Are Tissue Niche Need?
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Strategy :
Comparative analysis gene profiling and functional gene characterization
Highly differential expression genes
Cytokines and growth factors genes
Multi-lineage differentiation related genes
Target gene expression
Early gene expressions
Confirm the protein products
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Functional genomic characterization
ostogenic / chondrogenic / adipogenic /myogenic / neurongenic /
endothelial cell differentiation
Part 1. Multi-lineage differentiation related genes
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Molecular Analytic results suggest that BM-MSCs preferentially expressed functional genes differences from AD-MSCs in:
•Secretion of Hemagiogenic factors (LIF / Jagged-1/ BMP-4 / HGF / PIGF-1 / PIGF-2
/ HB-EGF ),
•Supply Homing/ mobilzing elements (:CD106(VCAM-1)/ jagged-1/ SDF-1), and
•Generation of ECM remodeling factors (mmp9/mmp1) for HS/PCs (CD34+, CD38-, and CXCR-4+)
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Highly differential expression of genes is primarily involved in
Growth factors /Extra cellular matrix molecules /Cell surface molecules /Receptors /
Suggest that the major difference between BM-MSCs and AD-MSCs : cell-cell interactions regulate or support tissue cells
▪
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1. The tissue cells homing and mobilization.
CD106 (VCAM-1) / SDF-1 / MMP-9/HGF
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Journal of Cellular biochem S 38:29-38 (2002)
BM-MSCs exppressed more key factors involved in Homing and mobilization of hematopoietic stem cells :CD106 / SDF-1 / MMP-9
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Hematopoiesis LIF / SDF-1 / BMP-4 / Jagged-1 / HGF
AngiogenesisHGF / PIGF-1 / PIGF-2 / HB-EGF
2. The tissue cells supporting.
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3. The ECM remodeling properties
ECM remodeling protease MMP-1 / MMP-9
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Our present study indicated the tissue specificity of mesenchymal stem cells exhists as analyzed by molecular characterization of their gene and protein expressions.
In addition to their cell surface phenotypic descriptions and multipotency examinations in vitro, this approach may be indispensable in further realizing the nature of tissue stem cell populations
Conclusions
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Thanks for Your Attensions
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Proerythroblast
MultipotentStem Cell
Self-renewal ?
Early ActingSCF FL Tpo
G-CSFIL3IL6IL7
IL11
Erythrocyte Platelet Neutrophil Monocyte Eosinophil Basophil
Macrophage Mast Cell
Mega-karyocyte
Myeloblast MonoblastEosinophilicMonoblast
BasophilicMonoblast
CFU-ECFU-G CFU-M CFU-Eo CFU-Baso
BFU-E CFU-Mega CFU-GM
CFU-G, E, M, Mega
EpoIGF-1
EpoIGF-1
Tpo
G-CSFGM-CSF
SCF IL3GM-CSF
GM-CSFM-CSF
GM-CSFIL5
IL5
IL3IL4
IL3IL4
IL3IL4GM-CSF
M-CSF
SCFIL3GM-CSF
SCFIL3IL6Tpo
SCFIL3IL6G-CSFGM-CSF
GM-CSFM-CSF
The Haematopoietic System
• Humoral Regulation
ModulatingIL1IL4
MIP-1TNFTGF
CLPsCMPs