Small Molecules and Hematopoietic Stem Cells

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Small Molecules and Hematopoietic Stem Cells

• Presenter Wang Lan

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Introduction

• Hematopoietic stem cells (HSCs)
• Multipotent stem cells
• Residing in the bone marrow
• Self-renew and differentiate into all blood
  lineages

Aggarwal R, Curr .Mol. Med, 2012, 12(1) 34-49
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HSC Location during the Murine Embryonic
Development
Aggarwal R, Curr .Mol. Med, 2012, 12(1) 34-49
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• Widely used in transplantation therapies to treat
  blood disorders of different etiologies
• The major bottleneck
• The difficulty to obtain sufficient HSC numbers
• Immunologically matched HSCs in the case of
  allogeneic transplantation

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HSC Self-Renewal Regulators
Walasek, MA, Ann. N.Y. Acad. Sci, 2012, 1266
138-50
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• Small molecule drugs
• Better understanding of signaling pathways that
  control cell fate
• Development of technologies for high-throughput
  screening
• Regulation more flexible
• Temporal control the inhibition
• or activation
• Finely tuned by delicately
• varying the concentrations or
• combinations

Langle D, ACS Chem Biol, 2014, 9(1) 57-71
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Small Compounds Screening Approaches

• Discovery-based chemical screens
• Probes overall mechanisms
• No requiring much of prior
• Knowledge of the targets
• being modulated
• Rationale-based chemical approach
• Hypothesis-driven
• Using mechanistically known small molecules

Li W, ACS Cell Res, 2013, 23 81-91
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Walasek, MA, Ann. N.Y. Acad. Sci, 2012, 1266
138-50
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Walasek, MA, Ann. N.Y. Acad. Sci, 2012, 1266
138-50
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Copper Chelator, TEPA

• TEPA-supplemented, long-term cytokine cultures
  significantly increased the number of CD34CD38-
  cells and enhanced NOD/SCID repopulating
  capacity.
• (Bae B, J.Nut, 1993)
• TEPA-cultured CB cells were coinfused with
  uncultured CB cells showed a safety of this
  approach in a phase I/II clinical trial. (Peled
  T, Exp, Hematol, 2004 Peled T, Exp, Hematol,
  2005)
• TEPA are under investigation in an ongoing phase
  II/III study. (Peled T, Cytotherapy, 2004 de
  Lima, Bone Marrow Transplant, 2008)

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Histone Deacetylase Inhibitor, HDACi

• HSCs could be modulated through epigenetic
  regulation

Preserve the HSC phenotype for murine and human
Valproic Acid
Maintain hmPBHSC
Chlamydocin
Improve maintenance of stem cells in culture
Trichostatin A
Upregulation of cell-intrinsic HSPC fate
regulators, such as HoxB4 and AC133
Seet L, Eur. J. Haematol, 2009, 82 124-32
Araki H, Blood, 2009, 109 3570-78 Milhem M,
Blood, 2004, 103 4102-10 Young JC,
Cytotherapy, 2004, 6 328-36
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StemRegenin 1, SR1

• Acryl hydrocarbon receptor antagonist
• Enhances human CD34 HSC cell amplification
• Potential mechanism
• AhR on the surface of hHSC implicates in
• pathways regulating hematopoiesis

Boitano AE, Science, 2010, 329(5997) 1345-48
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Other Compounds
All-trans Retinoic Acid (ATRA)
6-Bromoindirubin-3-Oxime (BIO)
Prostaglandin E2 (PGE2)
Promote HSC Expansion
Regulate HSC Self-renewal
Maintenance of HSC stemness
Walasek, MA, Ann. N.Y. Acad. Sci, 2012, 1266
138-50
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Thanks for Your Attention