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Small Molecules and Hematopoietic Stem Cells
Presenter: Wang Lan
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
HSC Location during the Murine Embryonic Development
Aggarwal R, Curr .Mol. Med, 2012, 12(1): 34-49
• 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
Walasek, MA, Ann. N.Y. Acad. Sci, 2012, 1266: 138-50
HSC Self-Renewal Regulators
• 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
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
Walasek, MA, Ann. N.Y. Acad. Sci, 2012, 1266: 138-50
Walasek, MA, Ann. N.Y. Acad. Sci, 2012, 1266: 138-50
Copper Chelator, TEPA
• TEPA-supplemented, long-term cytokine cultures significantly increased the number of CD34+CD38- 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)
•HSCs could be modulated through epigenetic regulation
Histone Deacetylase Inhibitor, HDACi
Valproic Acid Preserve the HSC phenotype for murine and human
Chlamydocin Maintain hmPBHSC
Trichostatin AImprove maintenance of stem cells in culture
Upregulation of cell-intrinsic HSPC fate regulators, such as HoxB4 and
AC133Seet 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
•Acryl hydrocarbon receptor antagonist
•Enhances human CD34+ HSC cell amplification
•Potential mechanism: AhR on the surface of hHSC implicates in pathways regulating hematopoiesis
StemRegenin 1, SR1
Boitano AE, Science, 2010, 329(5997): 1345-48
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
Thanks for Your Attention