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Specific Cell (Re-)Programming: Approaches and Perspectives

  • Chapter
  • First Online:
Engineering and Application of Pluripotent Stem Cells

Part of the book series: Advances in Biochemical Engineering/Biotechnology ((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.

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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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  1. Frauke Hausburg and Julia Jeannine Jung contributed equally to this work.

Authors and Affiliations

  1. Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), Department of Cardiac Surgery, Rostock University Medical Center, Schillingallee 69, 18057, Rostock, Germany

    Frauke Hausburg, Julia Jeannine Jung & Robert David

  2. Department Life, Light and Matter of the Interdisciplinary Faculty at Rostock University, Albert-Einstein-Strasse 25, 18059, Rostock, Germany

    Frauke Hausburg, Julia Jeannine Jung & Robert David

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  1. Frauke Hausburg
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  2. Julia Jeannine Jung
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  3. Robert David
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Correspondence to Robert David .

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  1. Leibniz Research Labs for Biotechnology, Hannover Medical School (MHH), Hannover, Germany

    Ulrich Martin

  2. Leibniz Research Labs for Biotechnology, Hannover Medical School (MHH), Hannover, Germany

    Robert Zweigerdt

  3. Leibniz Research Labs for Biotechnology, Hannover Medical School (MHH), Hannover, Germany

    Ina Gruh

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Hausburg, F., Jung, J.J., David, R. (2017). Specific Cell (Re-)Programming: Approaches and Perspectives. In: Martin, U., Zweigerdt, R., Gruh, I. (eds) Engineering and Application of Pluripotent Stem Cells. Advances in Biochemical Engineering/Biotechnology, vol 163. Springer, Cham. https://doi.org/10.1007/10_2017_27

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