Chemical approaches to stem cell biology and therapeutics

Abstract

Small molecules that modulate stem cell fate and function offer significant opportunities that will allow the full realization of the therapeutic potential of stem cells. Rational design and screening for small molecules have identified useful compounds to probe fundamental mechanisms of stem cell self-renewal, differentiation, and reprogramming and have facilitated the development of cell-based therapies and therapeutic drugs targeting endogenous stem and progenitor cells for repair and regeneration. Here, we will discuss recent scientific and therapeutic progress, as well as new perspectives and future challenges for using chemical approaches in stem cell biology and regenerative medicine.

Figure 1. Chemical approaches to stem cell biology and therapeutics

Chemical approaches are applied in vitro and in vivo to manipulate cell fate toward desired therapeutic applications, which include cell activation, expansion, differentiation, somatic lineage-specific trans-differentiation and iPSC reprogramming. The functional cells generated through chemical approaches could be used as the cell source for cell-based therapy. In addition, the chemical compounds that can regulate appropriate cell fate or function could be further developed as small molecule therapeutics for modulating endogenous cells underlying disease or injury conditions.

Figure 2. The structures and mechanisms of representative chemicals for cell fate modulation

Pluripotin or the combination of PD0325901 and CHIR99021 can support mESC self-renewal by inhibiting the differentiation-inducing signaling. Thiazovivin is a ROCK inhibitor that enhances hESC survival after dissociation. StemRegenin 1 enhances HSC self-renewal by inhibition of AhR. SB431542 (a TGFβ receptor inhibitor) or other small molecules inhibiting TGFβ signaling sustain primitive NSC self-renewal when combined with CHIR99021 and LIF; promote neural induction from PSC; or enhance reprogramming. IDE1 promotes differentiation of PSCs into definitive endoderm (DE). Indolactam V, a PKC activator, promotes differentiation of PSC-derived DE cells toward pancreatic lineage. KY02111, IWR-1endo and IWP2/4 can inhibit Wnt signaling through distinct mechanisms and facilitate cardiac specification of PSC-derived cardiac precursor cells. PluriSIn#1 is toxic specifically to pluripotent cells by inhibiting SCD1. Modulation of various epigenetic proteins, including HDACs, DNMTs, HMTs, HDMs, and signaling pathways, including Wnt, cAMP and PDK-1, can induce and enhance reprogramming. RasGAP: Ras GTPase activating protein; ERK1: extracellular signal-regulated kinase-1; MEK: Mitogen-activated protein/ERK kinase; GSK3: glycogen synthase kinase-3; ROCK: Rho-associated Kinase; AhR: aryl hydrocarbon receptor; TGFβ: transforming growth factor β; PKC: protein kinase C; SCD1: stearoyl-CoA desaturase-1; G9a: G9a histone methyltransferase; DNA MTase: DNA methyltransferase; LSD1: lysine-specific demethylase 1; DOT1L: DOT1-like, histone H3 methyltransferase; PKA: protein kinase A; PDK-1: 3´-phosphoinositide-dependent kinase-1;.

Figure 3. The structures and mechanisms of representative chemicals for modulating endogenous stem cells and tissue regeneration

CXCR4: C-X-C chemokine receptor type 4; VLA-4: very late antigen 4; DPP4: dipeptidylpeptidase IV; PGE2: prostaglandin E2; Cdc42: cell division control protein-42; CBFβ: core-binding factor β subunit;.