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Specific Cell (Re-)Programming: Approaches and Perspectives

  • Frauke Hausburg
  • Julia Jeannine Jung
  • Robert David
Chapter
Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE, volume 163)

Abstract

Many disorders are manifested by dysfunction of key cell types or their disturbed integration in complex organs. Thereby, adult organ systems often bear restricted self-renewal potential and are incapable of achieving functional regeneration. This underlies the need for novel strategies in the field of cell (re-)programming-based regenerative medicine as well as for drug development in vitro. The regenerative field has been hampered by restricted availability of adult stem cells and the potentially hazardous features of pluripotent embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Moreover, ethical concerns and legal restrictions regarding the generation and use of ESCs still exist. The establishment of direct reprogramming protocols for various therapeutically valuable somatic cell types has overcome some of these limitations. Meanwhile, new perspectives for safe and efficient generation of different specified somatic cell types have emerged from numerous approaches relying on exogenous expression of lineage-specific transcription factors, coding and noncoding RNAs, and chemical compounds.

It should be of highest priority to develop protocols for the production of mature and physiologically functional cells with properties ideally matching those of their endogenous counterparts. Their availability can bring together basic research, drug screening, safety testing, and ultimately clinical trials. Here, we highlight the remarkable successes in cellular (re-)programming, which have greatly advanced the field of regenerative medicine in recent years. In particular, we review recent progress on the generation of cardiomyocyte subtypes, with a focus on cardiac pacemaker cells.

Graphical Abstract

Keywords

Cardiovascular regeneration Cell fate conversion Direct reprogramming Lineage conversion Metabolic disorders Neurodegenerative disorders Regenerative medicine 

Abbreviations

(±)-BayK-8644

Ca2+ channel agonist

A83-01

TGF-β inhibitor

AA

Ascorbic acid

ACTN2

α-Actinin

ADSC

Adipose tissue-derived mesenchymal stem cell

AFP

α-Fetoprotein

Akt1

AKT serine/threonine kinase 1

ALB

Albumin

ALK5

TGFβ type I receptor kinase

ALP

Alkaline phosphatase

ANF

NPPA, natriuretic peptide A

APD

Action potential duration

APOA1

Apolipoprotein A1

AS8351

Iron chelator

ASC

Adult stem cell

Ascl1

Achaete-scute homolog 1

ATF5

Activating transcription factor 5

ATSC

Adipose tissue-derived mesenchymal stem cells

AV

Atrioventricular

Bcl2

B-cell lymphoma 2

BCT

Bioartificial cardiac tissue

bFGF

Basic fibroblast growth factor

bHLH

Basic helix-loop-helix

BIO

6-Bromoindirubin-3′-oxime, canonical Wnt activator

BIX01294

Diazepin-quinazolinamine derivative; histone-lysine methyltransferase inhibitor

Bmi1

BMI1 proto-oncogene, polycomb ring finger

BM-MSC

Bone marrow-derived mesenchymal stem cell

bpm

Beats per minute

Bry

Brachyury

CD166

ALCAM; activated leukocyte cell adhesion molecule

CEBPA

CCAAT/enhancer binding protein alpha

CF

Cardiac fibroblast

CHD

Congenital heart defect

CHIR

CHIR99021, GSK-3 inhibitor, Wnt activator

CM

Cardiomyocyte

C-MYC

MYC proto-oncogene, bHLH transcription factor

CPC

Cardiac progenitor cell

CRM

Cardiac reprogramming medium

CS

Conduction system

CT99021

SHH and the GSK3β inhibitor

cTnI

Troponin I3, cardiac type

cTnT

Troponin T2, cardiac type

Cx

Gap junction protein

CYP

Cytochrome P450

DAPT

N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester

DCX

Newborn neuron

DES

Desmin

DF

Dermal fibroblast

DFSC

Dental follicular-derived mesenchymal stem cell

DLX1

Distal-less homeobox

DMEM/F12

Dulbecco’s modified eagle medium: nutrient mixture F-12

DMD

Dystrophin

EAD

Early after depolarizations

EBIO

1-EBIO; KCa2/3 channel activator

EGF

Epidermal growth factor

EPC

Endothelial progenitor cell

EPDC

Epicardium-derived cell

ESC

Embryonic stem cell

FFV

FGF2, FGF10 & VEGF

FGF

Fibroblast growth factor

FHF

First heart field

FLF

Fetal limb fibroblast

forskolin

Adenylyl cyclase activator

FOX

Forkhead box

GABA

Gamma-aminobutyric acid

GAD67

Glutamate decarboxylase 1

Gata4

GATA binding protein 4

GF

Gingival fibroblast

Glut2

SLC2A2; solute carrier family 2 member 2

GMT

Gata4, Mef2c & Tbx5

GMTH

Gata4, Mef2c, Tbx5 & Hand2

GO6983

PKC inhibitor

GSK126

Selective EZH2 methyltransferase inhibitor

Hand2

Heart and neural crest derivatives expressed 2

HC

Hepatocytes

hCMVEC

Human cardiac microvascular endothelial cell

HCN

Hyperpolarization-activated cyclic nucleotide channel

hEF

Human embryonic fibroblast

HFF

Human foreskin fibroblast

hiPSC-ECM

Induced pluripotent stem cell-derived embryonic cardiac myocyte

HNF

Hepatic nuclear factor

I-BET151

Bromodomain and extra-terminal domain family inhibitor

If

Funny current

iPSC

Induced pluripotent stem cell

Isl1

ISL LIM homeobox 1

ISX9

Neurogenesis inducer

ITS

Insulin-transferrin-selenium

JAK inhibitor I

Janus-Associated Kinase Inhibitor I

JNJ10198409

ATP-competitive inhibitor of platelet-derived growth Factor receptor tyrosine kinase

JNK

C-Jun N-terminal kinases

KLF4

Kruppel like factor 4

LDL

Low-density lipoprotein

LDN193189

BMP4 inhibitor

LF

Lung fibroblast

Lhx6

LIM homeobox protein 6

LIF

Leukemia inhibiting factor, JAK/STAT activator

LMX1A

LIM homeobox transcription factor 1 alpha

L-MYC

MYCL proto-oncogene, bHLH transcription factor

lncRNA

Long noncoding RNA

LVEF

Left ventricular ejection fraction

Ly294002

Phosphoinositide 3-kinase (PI3K) inhibitor, TGF-β activator

MafA

v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A

Map2

Microtubule-associated protein 2

MAPK

Mitogen-activated protein kinase 1

MEF

Mouse embryonic fibroblast

Mef2c

Myocyte enhancer factor 2C

MF

Myofibroblast

Mhc

Myosin heavy chain

MI

Myocardial infarction

miR

microRNA

MLC2v

Myosin, light polypeptide 2, regulatory, cardiac, slow

MM3-GHT

Combination of Gata4, Hand2, Tbx5, and the fusion gene MM3 between Mef2c and the transactivation domain of MyoD

MRI

Magnet resonance imaging

MSC

Mesenchymal stem cell

MYH3

Embryonic myosin

MYH6

Myosin heavy chain 6, cardiac muscle, alpha

MyHC

Myosin heavy chain 6

MyoD

Myogenic differentiation 1

MYOG

Myogenin

MYT1L

Myelin transcription factor 1 like

N2

Cysteine proteinase inhibitor

NeuN

Neuronal nuclei

NeuroD1

Neurogenic differentiation 1

NEUROD2

Neuronal differentiation 2

NFF

Neonatal foreskin fibroblast

NG2

Oligodendrocyte precursor

Ngn

Neurogenin

NKX

Homeobox protein

NMDA

N-Methyl-d-aspartate

NNCF

Neonatal cardiac fibroblast

NNF

Neonatal fibroblast

NRVM

Neonatal rat ventricular myocyte

NURR1

Nuclear receptor related 1 protein

OAC2

Oct4-activating compound 2

OB

Osteoblast

OC

Osteocyte

OCT4

POU class 5 homeobox 1

PC

Pacemaker cell

PD0325901

MEK1/2 inhibitor

Pdx1

Insulin promoter factor 1

pkc

Protein kinase C

PM

Pacemaker

PROX1

prospero homeobox 1

PSC

Pluripotent stem cell

Purmo

Purmorphamine

PV

Parvalbumin

Repsox

Inhibitor of the TGF-β type 1 receptor

ROCK

Rho-associated protein kinase

RUNX2

Runt related transcription factor 2

Ryr2

Ryanodine receptor 2

SAG

Smoothened agonist

SAN

Sinoatrial node

SB431542

TGF-β inhibitor

SC

Stem cell

SC1

Pluripotin, dual selective inhibitor of the ERK1 and Ras-GAP signaling pathways

SCD

Sudden cardiac death

SCN5A

Sodium channel, voltage-gated, type V, alpha subunit

SERPINA1

Serpin family A member 1

SHF

Second heart field

SHH

Sonic hedgehog

Shox2

Short stature homeobox 2

shRNA

Small hairpin RNA

siRNA

Small interfering RNA

SIRPA

Signal regulatory protein alpha

SLC1A2

Solute carrier family 1 member 2

Sox

Sex determining region Y-box 2

SP600125

JNK inhibitor

SR-3677

ROCK inhibitor

SSS

Sick sinus syndrome

STAT3

Signal transducer and activator of transcription 3

SU16F

Platelet-derived growth factor receptor β inhibitor

SV40

Simian vacuolating virus 40

Tbx

T-box factor 18

TF

Transcription factor

TGF-β

Transforming growth factor-β

THF

Tertiary heart field

Tnnt2

Troponin T2, cardiac type

TTF

Tail tip fibroblast

TTNPB

Analog of retinoic acid

TUBB3

β-III-tubulin

Tuj1

Neuron-specific class III beta-tubulin

Tzv

Thiazovivin

UNC0638

Histone methyltransferase inhibitor

VEGF

Vascular endothelial growth factor

VGLUT1

Vesicular glutamate transporter 1

VPA

Valporic acid

XAV939

Wnt inhibitor

Y-27632

ROCK inhibitor

α-MHC

Myosin heavy chain 6

βMe

β-Mercaptoethanol

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Frauke Hausburg
    • 1
    • 2
  • Julia Jeannine Jung
    • 1
    • 2
  • Robert David
    • 1
    • 2
  1. 1.Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), Department of Cardiac SurgeryRostock University Medical CenterRostockGermany
  2. 2.Department Life, Light and Matter of the Interdisciplinary Faculty at Rostock UniversityRostockGermany

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