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