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Table 2 Reprogramming human fibroblasts into neurons using small molecules since 2012

From: How to reprogram human fibroblasts to neurons

Target Cell Type

Morphogens or Small molecules

Reprogramming Mechanism

Effects on neural cells induction

Reprogramming factors

Effects on neural cells induction

References

Neurons

CHIR99021

GSK3β inhibition

Suit the branch of neurons’ and axons’ growth

ASCL1, NGN2

Improve positive rate of Tuj1+ cells

Ladewig et al. 2012 [20]

SB431542

ALK5 inhibition (Activin/Nodal/TGFβ pathway inhibition)

Unknown

  

NOGGIN, LDN-193189

ALK2/3/6 inhibition (BMP/SMAD signaling inhibition

Unknown

  

Cholinergic neurons

Forskolin

cAMP activation

Induce massive production of Tuj1+ cells, which have neuron-like morphology

NGN2/NGN2+

Activate a cohesive pathway that determines a more homogenous neuronal subtype (cholinergic neuron)

Liu et al. 2013 [50]

Dorsomorphin

BMP inhibition

Promote neuron survival and maturation cooperating with FSK, while DM itself does not affect neuron transformation

SOX11+

Promote the survival and maturation of neurons but does not specify the neuron subtype

   

FGF2

Improve reprogramming efficiency significantly

Neurons

NOGGIN

TGFβ inhibition

Unknown

NGN2-2A-ASCL1

Unknown

Mertens et al. 2015 [101]

LDN193189, SB431542, A83-01

ALK2/3/4/5/7 inhibition

 

CHIR99021,

GSK3β inhibition,

Forskolin, DBcAMP

cAMP activation

Glutamatergic neurons

Valproic acid

HDAC inhibition

Activate cells through epigenetic modification

–

–

Hu et al. 2015 [22]

CHIR99021

GSK3β inhibition

Promote the transformation of human fibroblasts to neurons and induce dopamine neurons to human ESCs

Repsox

TGFβ inhibition

Improve neuron survival

Forskolin

cAMP activation

Enable Ngn2 to convert human fibroblasts into cholinergic neurons

SP600125

JNK inhibition

Facilitate the neural reprogramming of AHDF transduced with OCT4 alone

G06983

PKC inhibition

Improve human pluripotent stem cells and induces neuritogenesis of Neuro-2a cells

Y-27632

ROCK inhibition

Maintain the viability of pluripotent stem cells and neurons

Dorsomorphin

BMP inhibition

Promote the survival and maturation of neurons

Motor neurons

Forskolin Dorsomorphin

Unknown

All increase the population of Tuj1+ cells reprogramming from fibroblasts

NGN2-IRES-GFP-T2A-SOX11, ISL1-T2A-LHX3

Unknown

Liu et al. 2016 [92]

GABAergic Neurons

CHIR99021, SB431542, Db-cAMP

Unknown

Improve the efficiency of neuron differentiation

Order PTB knockdown and nPTB knockdown

Induce the transcription of miR-9, the activation of miR-9 made the induced neuron-like cells progress to functional neurons

Xue et al. 2016 [53]

PTB knockdown and BRN2 expression

Facilitate the expression of MAP2 in neurons and promote the influx of Ca2+

Neurons

Kenpaullone (WL12)

GSK3β inhibition

Increase reprogramming efficiency

ASCL1, BRN2, MYT1L

Unknown

Pfisterer et al. 2016 [55]

PGE2

cAMP/PKA modulator

Increase reprogramming efficiency

Forskolin

cAMP activation

Unknown

BML 210

HDAC inhibition

Facilitate the recovery of pluripotency in reprogramming

Aminoresveratrol Sulfate (EL38)

SIRT1 activation

Unknown

PP2

Src kinase inhibition

Skip the SOX2 pathway, activate sirtuins complement and promote Klf4 expression

Neurons

CHIR99021, SB431542, NOGGIN, LDN193189, Valproic acid

Unknown

Unknown

ASCL1, BRN2

Unknown

Drouin-Ouellet et al. 2017 [102]

Shrigley et al. 2018 [103]

Marina et al. 2020 [56]

SHREST

miR-9 activation, miR-124 activation

Motor neurons

Kenpaullone

GSK3β inhibition; HPK1 / GCK-like kinase inhibition

Enhance the binding of other small molecules to its target

–

–

Qin et al. 2018 [7]

Later change to CHIR99021

cAMP activation

Promote the growth of neurons, which is weaker than that of Kenpaullone

Forskolin

ROCK inhibition

Unknown

Y27632

Unknown

Unknown

Purmorphamine

Unknown

Unknown

RA

Unknown

Improve the differentiation from pluripotent stem cells to motor neurons through the activation of RA and SHH signals

Neurons

Valproic acid

Unknown

Unknown

–

–

Wan et al. 2018 [23]

CHIR99021

Glycogen synthase kinase-3β inhibition

Improve the conversion of human fibroblasts to neurons

 

DMH1

BMP inhibition

Improve the conversion of human fibroblasts to neurons

Repsox

Transforming growth factor-β inhibition

Improve the conversion of human fibroblasts to neurons

Forskolin

ROCK2 inhibition

Improve migration of neural crest cells; enable neurogenin 2 to convert human fibroblasts into cholinergic neurons

Y-27632

Rho kinase inhibition

Facilitate the maintenance of pluripotent stem cells and neuron survival

SP600125

JNK inhibition

Enhance the neuronal conversion of fibroblasts

Neurons

CHIR99021

GSK3 inhibition

Unknown

ASCL1, BRN2, ShREST

Unknown

Villanueva-Paz et al. 2019 [104]

Noggin

BMP inhibition

Unknown

Valproic acid

HADC inhibition

Unknown

SB431542, LDN193189

Unknown

A neural fate inducing factor

Dopaminergic neurons

CHIR99021, Purmorphamine, Y27632

Unknown

Unknown

ASCL1, NURR1, LMX1A, miR-124, p53 shRNA

Unknown

Jiali et al. 2020 [105]