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Title: STEM CELLS: OPPORTUNITIES AND CHALLENGES


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  • STEM CELLS OPPORTUNITIES AND CHALLENGES
  • Center for Stem Cell Biology Regenerative
    Medicine
  • UMass Memorial Musculoskeletal Center of
    Excellence

3
STEM CELLS OPPORTUNITIES AND CHALLENGES
  • Biology of stem cells and applications for
    treatinghuman disease
  • UMASS initiatives in developing stem cell-based
    therapy

4
STEM CELLS OPPORTUNITIES AND CHALLENGES (Contd)
  • Biology of stem cells and applications for
    treatinghuman disease
  • UMASS initiatives in developing stem cell-based
    therapy

5
What is a Stem Cell?
  • What is a Stem Cell?
  • What are different types of stem cells?
  • What is the promise of stem cell research?

6
Stem Cells What are they?
7
Development of a Human Embryo
Totipotent
Pluripotent
Lineage Commitment
Single-cell embryo
3-day embryo
5-7day embryo
4-week embryo
6-week embryo
Isolation of Embryonic Stem Cells
8
Properties of Embryonic Stem Cells
Isolated from an early stage embryo
Exhibit normal karyotype
Express Markers
Pluripotent
9
The Promise of Stem Cell Research
10
Why Stem Cells
11
Timeline of Stem Cell Research
1956First successful bone marrow transplant
1998Human embryonic stem cells isolated at Univ.
Wisconsin
1981Embryonicstem cells are isolated from mouse
blastocysts
2007iPS cells first developed
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Types of Stem Cells
  • Adult Stem Cells
  • Embryonic Stem Cells (hESC)
  • Somatic Cell Nuclear Transfer (SCNT) Stem Cells
  • Induced Pluripotent Stem (iPS) Cells

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Adult Stem Cells
Where have adult stem cells been found?
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Adult Stem Cells (contd)
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Lineage Committed Stem Cells Support Bone
Formation (Development and Tissue Regeneration)
OC OP Collagenase
AP BSP Collagen Fra2/JunB
Histone Fibronectin Collagen c-Fos/c-Jun TGFb1 Ost
eopontin
BAX p53 c-Fos Msx2
Matrix Maturation
Lineage Commitment
Proliferation
Mineralization
Self Renewal
Glucocorticoid Vitamin D BMP
BMP TGFb
BMP TGFb
Vitamin D TGFb
Stem Cell
Osteoproginator
Pre-Osteoblast
Osteocyte
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Embryonic Stem Cells
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Human Embryonic Stem Cells (hES Cells)
Human ES cell colony on mouse fibroblast feeders
Human Blastocyst
Inner Cell Mass (ICM)
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hES Cells (contd)
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Derivation of induced Pluripotent Stem Cells
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Induced Pluripotent Stem Cells
Reprogramming Correcting Genetic Defect
Reprogramming
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iPS Cells
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Comparative Properties of Stem Cells
  • Embryonic Stem Cells Indefinite growth
    Potential to differentiate into any cell type
  • Lineage-Specific Stem Cells Limited growth
    Potential to differentiate into defined cell
    types
  • Cancer Stem Cells Indefinite growth Cannot
    differentiate into a defined cell type

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Why so many types of stem cells? Because none are
perfect.
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UMASS Initiatives in Developing Stem
Cell-Based Therapy
  • A Collaboration of
  • UMASS Center for Stem Cell Biology
    Regenerative Medicine
  • UMASS Memorial Musculoskeletal Center for
    Excellence

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UMASS Contributions to two Rate-LimitingParamete
rs of Stem Cell Control
  • Mechanisms that regulate rapid and infinite
    proliferation of stem cells
  • Mechanisms that establish and maintain lineage
    commitment following differentiation

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Genetic and Epigenetic Regulation
  • Genetic Control DNA-encoded Regulatory
    Information.Epigenetic Control Regulatory
    Information for cell structure, function and
    specificity NOT encoded in DNA that IS
    transmitted to progeny cells during cell
    division.

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Genetic and Epigenetic Regulation
  • Genetic Control

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Genetic and Epigenetic Regulation
  • Epigenetic Control
  • Histone Code

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Genetic and Epigenetic Regulation
  • Epigenetic Control
  • Regulatory Factor Architectural Signature

Transcriptional Suppression
Maximal Expression
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  • Mechanisms that control rapid and infinite
    proliferation of stem cells
  • Mechanisms that establish and maintain lineage
    commitment following differentiation

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The Mammalian Cell Cycle
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An Abbreviated Cell Cycle in Human Embryonic Stem
Cells
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Dynamics of Combinatorial Organizationand
Assembly of Regulatory Machinery inNuclear
Microenvironments
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  • Mechanisms that control rapid and infinite
    proliferation of stem cells
  • Mechanisms that establish and maintain lineage
    commitment following differentiation

35
Lineage-Specific Retention of RegulatoryMachinery
for Cell Fate DeterminationDuring Mitosis
  • Post-mitotic gene expression requires restoration
    of nuclear organization and assembly of
    regulatory complexes.
  • Two models
  • Degradation, re-synthesis, and assembly/organizat
    ion
  • Retention and partitioning

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Runx2 A Transcription FactorInvolved in Lineage
Commitment andRequired for Osteogenesis in vivo
37
Contributions of Runx Factors to Genetic and
Epigenetic Control Scaffolds for Spatial
Organization of Promotor Regulatory Complexes
(P/DNA and P/P)
X
Montecino et al (1994) Biochemistry, 33
384 Javed et al (1999) Mol Cell Biol,
197491 Gutierrez et al (2007) J Biol Chem,
282-9445
38
Re-organization of Regulatory MachineryDuring
Mitosis
MITOSIS
INTERPHASE
Young et al (2007) Nature, 445 442
39
Runx2 Remains Stably Associated withMitotic
Chromosomes
Young et al (2007) PNAS, 104 3189
40
Chromosomal Association of Runx2 is Allelic
Runx Foci
Young et al (2007) Nature, 445 442
41
A Multi-Dimensional Approach to Understand Stem
Cell Biology and Therapeutic Potential
  • Stem cells exhibit a shorter cell cycle
    sustained growth and unrestricted availability.
  • Cell fate, lineage commitment and maintenance
    require the combined contributions of genetic and
    epigenetic mechanisms in nuclear
    microenvironments during and following cell
    division.

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Challenges and Opportunities of Stem Cell
Research
  • Moral and ethical considerations
  • Immuno compatibility
  • Procedure-related compromises (e.g., insertional
    mutagenesis, tumorigenesis)
  • Retention of genetic basis for diseases

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Success Stories with Stem Cells
  • Bone Marrow Transplantation - Cancer -
    Hemotological Diseases
  • Cardio-vascular Stem Cells
  • Neurological Stem Cells - Spinal Cord
    Injury - Adult Macular Degeneration
  • - ALS
  • Skeletal Reconstruction

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Acknowledgements
Members of the UMASS Center for Stem Cell Biology
Regenerative MedicineMembers of the UMASS
Memorial MusculoskeletalCenter of
ExcellenceJanet L. Stein Jane B. Lian Andre van
WijnenKlaus A. Becker Prachi Ghule Matthew
MandelliveDaniel YoungSayyed Kaleem Zaidi
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