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TGFβ: The TGFβ superfamily members are major regulators of self-renewal and differentiation to mesendodermal lineages. p38 / p53: p38 MAPK is activated in response to cellular stresses, and influences apoptosis and cellular differentiation. p53 is activated in Pathway Activators: IDE1, IDE2; Pathway Inhibitors: SB431542, LY364947, RepSox, Dorsomorphin, LDN193189 response to cellular stresses and regulates growth arrest, apoptosis and/or DNA repair. Inhibition of p53 is used to facilitate reprogramming. Pathway Inhibitors: BIRB-796, SB202190, SB203580, Cyclic Pifithrin-α, Pifithrin-μ Hedgehog: The Hedgehog pathway is important in the differentiation of mesenchymal subtypes (e.g. osteocytes) and in neural subtypes (e.g. dopaminergic neurons). FGF: FGF signaling via MEK/ERK is critical for self-renewal and proliferation of human PSCs. However, other receptor tyrosine kinases can Pathway Activator: Purmorphamine; Pathway Inhibitors: Cyclopamine, HPI-1 also act through the MEK/ERK and PI3K signaling pathways. Pathway Activators: Pyrintegrin, PS-48; Pathway Inhbitors: Pluripotin, PD0325901, PD98059, Reversine IWP-2 WNT: The WNT pathway regulates differentiation to the mesoendodermal lineages, induces self-renewal of PSCs, and aids in reprogramming. IWP-3 Pathway Activators: BIO, CHIR99021, Kenpaullone, SB216763; Pathway Inhibitors: IWP-2, IWP-3, IWP-4, XAV939, IWR-1-endo, KY02111; cAMP: cAMP is a second messenger important to reprogramming and differentiation to many subtypes. Pathway Modulators: IQ-1, ID-8 Pathway Activators: Prostaglandin E2, Forskolin, EHNA, IBMX; Pathway Inhibitor: HA-100 PCN IWP-4 Small Molecules, Big Impact Notch: The Notch pathway is activated when Delta or Jagged ligands on neighboring cells activate cleavage of the receptor, releasing the PKC: The PKC family of kinases is commonly activated by diacylglyercol (DAG) and calcium, and is involved in several signaling pathways Notch intracellular domain (NICD). The Notch pathway plays a role in specifying neural subtypes. that can regulate differentiation. (PORCUPINE) Pathway Inhibitors: DAPT, LY411575 Pathway Activators: Prostaglandin E2, (-)-Indolactam V; Pathway Inhibitors: (+)-Bay K8644, HA-100, Gö6983 In Pluripotent Stem Cell Research WNT RHO/ROCK: The Rho pathway regulates cytoskeletal dynamics and plays an important role in migration and apoptosis. Loss of cadherin or Epigenetics: Epigenetic marks such as acetylation (Ac) of histones and methylation (Me) of histones or DNA serve to induce or inhibit gene integrin binding activates the Rho pathway in human PSCs leading to anoikis. expression in a heritable manner. Global changes in epigenetic marks are critical for reprogramming. Pathway Inhibitors: Pyrintegrin, Y-27632, Thiazovivin, (-)-Blebbistatin DNA Methyltransferase Inhibitors: 5-Azacytidine, RG108, Zebularine; Histone Methyltransferase Inhibitors: 3-Deazaneplanocin A, Whether to affect self-renewal, survival, or differentiation of pluripotent BIX01294; Histone Demethylase Inhibitor: Tranylcypromine; Histone Acetyltransferase Inhibitor: Garcinol; Histone Deacetylase stem cells (PSCs), or to aid reprogramming to an induced pluripotent Inhibitors: Sodium Butyrate, Trichostatin A, Valproic Acid stem cell state, the right small molecule can transform a research project. STEMCELL Technologies offers small molecules that are being SMALL MOLECULES are available from STEMCELL Technologies. widely used in high impact research to target the key pathways in stem cell biology. For more information and examples of how these WNT DELTA JAGGED (EXTRACELLULAR MATRIX) CADHERIN Stress molecules are being used in pluripotent stem cell research, visit ECM FGF www.stemcell.com/smallmolecules. PYRINTEGRIN HH 28095 2 1 NOTCH PURMORPHAMINE CADHERIN INTEGRIN PROSTAGLANDIN E2 BMP FRIZZLED NICD FGFR SMO

TGFβ1 NODAL γ-SECRETASE PATCHED RHO PD173074 CYCLOPAMINE ACTIVIN BMPRII MKK3/6 EP3 BMPRI Y-27632 RAS ALK2/3/6 DAPT THIAZOVIVIN LY294002 EP2/4 LY411575 BIRB-796 XAV939 DSH IWR-1-ENDO SB202190 PI3K EP1 2+ βRII Ca TGF HPI-1 ROCK SB203580 PS-48 PD0325901 βRI RAF PD98059 TGF (-)-BLEBBISTATIN ALK4/5/7 DORSOMORPHIN TNKS1/2 BIO REVERSINE LDN193189 CHIR99021 RAS-GAP KENPAULLONE p38 MAPK PDK1 SB216763 (ADENYLYL CYCLASE) ANOIKIS AC ) ( MEK1/2 MYOSIN AXIN SB431542 SMAD ACTIN 1/5/8 GSK3 LY364947 GLI AKT PLURISIN-1 p53 REPSOX APC PLURIPOTIN FORSKOLIN DAG Ca2+ SMAD STEAROYL-CoA PKA 2/3 NICD SCD1 EHNA (+)-BAY K8644 IQ-1 ID-8 IBMX mTOR GSK3 cAMP PDE2 DEXAMETHASONE OLEOYL-CoA ERK1/2 βCAT DYRK APOPTOSIS CYCLIC PIFITHRIN-α SMAD4 PP2A PIFITHRIN-µ STAUPRIMIDE (-)-INDOLACTAM V

NME2

HA-100 PKC CBP TFs (TRANSCRIPTION FACTORS) TFs TFs TCF/LEF GR βCAT (GLUCOCORTICOID RECEPTOR) p300 NICD TFs Gö6983 Me GLI p38 SMAD MAPK ERK SMAD DZNEP EZH2 Me SMAD4 DNMTs Other Small Molecules BIX01294 G9a Glucocorticoid Pathway Activator: Dexamethasone Retinoid Pathway Activators: 9-cis Retinoic Acid, RXR All-Trans Retinoic Acid, CD437, TTNPB NME2 9-CIS RETINOIC ACID Ac HIF-1 Pathway Inhibitor: CAY10585 TRANYLCYPROMINE LSD1 NME2 Pathway Inhibitor: Stauprimide GR RAR 5-AZACYTIDINE HDACs Small molecules with undefined molecular mechanisms GR of action in stem cell biology can be used for RG108 reprogramming (OAC1), promoting differentiation of ZEBULARINE cardiomyocytes (Cardiogenol C) or self-renewal of ALL-TRANS RETINOIC ACID HATs human PSCs (Gatifloxacin, Sinomenine). CD437 SODIUM BUTYRATE CAY10585 TTNPB TRICHOSTATIN A GARCINOL HIF-1α VALPROIC ACID

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Copyright © 2018 by STEMCELL Technologies Inc. All rights reserved including graphics and images. STEMCELL Technologies & Design, STEMCELL Shield Design, Scientists Helping Scientists, an integrated workflow with the Erythroid Progenitor Reprogramming Kit (Cat #05924) or TeSR™-E8™ (Cat #05940), a simplified, xeno-free maintenance medium for hPSCs STEMdiff™ APEL™ and APEL™-LI (Cat #05210/05211) lineage-neutral media for customization of mesodermal ReproTeSR, STEMdiff, and APEL are trademarks of STEMCELL Technologies Canada Inc. TeSR, E7, E8, and mTeSR are trademarks of WARF. All other trademarks are the property of their respective holders. CD34+ Progenitor Reprogramming Kit (Cat #05925) differentiation protocols by adding cytokines or small molecules