Small Molecule-Induced Pancreatic β-Like Cell Development: Mechanistic Approaches and Available Strategies
Abstract
:1. Introduction
2. Small Molecules
3. Signaling Pathways
4. Protocols for the Differentiation of PSCs/iPSCs/MSCs into Functional Pancreatic β-Like Cells in a Stepwise Manner
4.1. Differentiation of Stem Cells into Definitive Endoderm: Activin-A and CHIR99021
4.2. Posterior Gut Tube: KGF
4.3. Pancreatic Endoderm: RA, LDN, SB431542, and SANT-1
4.4. Pancreatic Progenitors: DAPT and TPB
4.5. Endocrine Progenitors: Nicotinamide, N-acetyl Cysteine, and Exendin-4
5. Efficacy of Small Molecules-Induced Insulin Producing β-Like Cells
6. Reprogramming
6.1. Reprogramming of Pancreatic Exocrine Cells into β-Like Cells
6.2. Reprogramming of Acinar and Duct Cells
6.2.1. Acinar Cells to Pancreatic β-Like Cell Induction
6.2.2. Duct Cells Reprogrammed into Pancreatic β-Like Cell
6.3. α-Cell to β-Like Cell Reprogramming
7. Ectopic Expression
7.1. Ectopic Expression of PAX4
7.2. Ectopic Expression of GIP
7.3. Ectopic Expression of PDX1
7.4. Ectopic Expression of PDX1 and NKX6.1
7.5. SIRT5 (Sirtuin 5) Regulates Pancreatic β-Like Cell Proliferation and Insulin Secretion
7.6. Ectopic Expression of PDX1, NGN3, MAFA
8. Bio-Engineering and 3D-Printing Technology
8.1. Microenvironment Deliberation
8.2. Engineering a 3D Niche for Pancreatic Cells
8.3. ECM Scaffold
8.4. Vascularization and Encapsulation Technology
8.5. Amikagel Based Platform
8.6. Organ on Chip
9. Endothelial Cell Coculture
10. Expected Outcomes
- 1)
- Development of cheaper, more efficient, and faster protocols for the pancreatic lineage.
- 2)
- Resolution of microenvironmental issues by using bio-scaffolds and bio-printing.
- 3)
- A homogenous or pure population of pancreatic β-like cells is expected to be obtained.
- 4)
- Attainment of an increased number of insulin-positive cells with long-term in vitro and in vivo viability.
- 5)
- Development of highly potent pancreatic β-like cells in vitro with the ability to be preserved for longer durations without the loss of cellular and functional properties.
- 6)
- Preclinical studies need to follow, including investigations of blood glucose regulation after transplantation and immune protection methods.
- 7)
- Finally, achieving a life-long cure for diabetes by utilizing differentiated/reprogrammed/bioengineered stem cells without causing any ill effects.
11. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
2D | Two dimensional |
3D | Three dimensional |
ALK5iII | Activin receptor-like kinase 5 inhibitor II |
ASCs | Adult stem cells |
bFGF | Basic fibroblast growth factors |
BMP | Bone morphogenic protein |
DAPT | N-[N- (3,5-difluorophenacetyl)-L-alanyl-S-phenylglycine t-butyl ester |
Db-cAMP | Dibutyryl-cyclic AMP |
DE | Definitive endoderm |
DM | Diabetes mellitus |
ECCs | Endocrine cell clusters |
ECM | Extracellular matrix |
ECs | Endocrine cells |
EGF | Epidermal growth factor |
EPs | Endocrine progenitors |
FAB | bFGF, Activin-A and BMP4 |
GIP | Glucose-dependent insulinotropic polypeptide |
GLP1 | Glucagon-like peptide-1 |
GLUT1/2 | Glucose transporter ½ |
GSIS | Glucose stimulated insulin secretion |
GSK-3 β | Glycogen synthase kinase-3 beta |
hAFSC | Human amniotic fluid-derived stem cells |
hESCs | Human embryonic stem cells |
HGF | Hepatocyte Growth Factor |
hiPSCs | Induced pluripotent stem cells |
hPSCs | Human pluripotent stem cells |
ITS-X | Insulin, Transferrin, Selenium, Ethanolamine solution |
KGF | Keratinocyte growth factor |
NME2 | Non-metastatic cells 2 |
pdECM | Pancreatic tissue derived ECM |
PE | Pancreatic endoderm |
PGT | Posterior gut tube |
PI3K | Phosphoinositide 3-kinases |
PKC | Protein kinase C |
PPs | Pancreatic progenitors |
RA | Retinoic acid |
SHH | Sonic hedgehog |
SIRT | Sirtulins |
T3 | T3 Triiodothyronine |
TGF-β1 | Transforming growth factor beta 1 |
TPB | (((2S,5S)-(E,E)-8-(5-(4-(trifluoromethyl)phenyl)-2,4 pentadienoylamino)benzolactam) |
UCP2 | Uncoupling protein 2 |
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Stem Cell Source | Protocol | DE Markers (%) | PE Markers PDX+ (%) | PPs Markers (%) | Insulin Producing Cell INS+/C- Peptide+/GCG+ (%) | In vivo Efficacy: Glucose Homeostasis Restoration | GSIS | References |
---|---|---|---|---|---|---|---|---|
hESCs | Day 1–2: Activin A+WNT3A. Day 3–5: TGF-βi+KGF. Day 6–8: Noggin+RA+Cyclopamine. Day 9–10: EGF+KGF+Noggin. Day 11–20: TBP+ALKi+Noggin | NA | > 88% PDX1+ | 80% NKX6.1+/PDX1+ | 92% NKX6.1+/C-peptide+ | √ | In vitro √; In vivo √ | [15] |
hESCs, hiPSCs | Day 1: Activin A+CHIR. Day 2: Activin A. Day 4–6: KGF. Day 7–8: KGF+SANT1+RA+LDN+PdBU. Days 9–13: KGF+SANT1 +RA. Day 14–16: SANT1+RA+XXI+ ALK5iII+T3+Betacellulin. Day 18–20: RA+ XXI+ALK5iII+T3+Betacellulin. Day 21–35: ALK5iII+T3 | >95% SOX17+ | >85% PDX1+ | >55% NKX6.1+/PDX1+ | 8% C-peptide+/GCG+ | √ | In vitro √; In vivo √ | [17] |
hiPSCs | Day 1–3: Activin A+CHIR+WNT3A. Day 4–10: Noggin+Dorsomorphin+RA+SB431542. Day 11–21: Forskolin+Dexamethasone+ALK5iII+Nicotinamid. | 75% SOX17+/ FOXA2+ | NA | 72% PDX1+ | 8–16% INS+ | NA | In vitro √ | [19] |
hESCs | Day 1: Activin A+Li+CHIR. Day 2–5: Activin A. Day 6–11: RA+Dorsomorphin+SB431542+KAAD-Cyclopamine+FGF2. Day 12–15: DAPT+Dorsomorphin+SB431542 +Ascorbic acid. Day 16–23: Db-cAMP+Exendin-4+Dorsomorphin+SB431542+Nicotinamide+Ascorbic acid | >94% CXCR4+ | 93% PDX1+ | NA | NA | √ | In vitro √; In vivo √ | [22] |
hESCs | Day 1–3: GDF8+GSK3-βi. Day 4–5: FGF7+VitC. Day 6–10: FGF7+VitC+RA+ SANT+TPB+LDN. Day 11–13: SANT+RA+ ALK5iII+T3+LDN. Day 14–28: ALK5iII +T3+LDN+GSiXX. Days 28–43: ALK5iII +T3+N-Cys+AXLi. | NA | NA | 76% | 31–38% NKX6.1+/INS+ 21% NKX6.1+/GCG+ | √ | In vivo √ | [23] |
hiPSCs | Day 1–2: CHIR+FGF2+Activin-A+BMP4. Day 3–5: FGF2+Activin-A+BMP4. Day 6–7: FGF2+FGF7+EC23+SB431542+Dorsomorhin+SANT1. Day 8–11: FGF2+EC23+SB431542+ Dorsomorphin+SANT1. Day 12–14: FGF10 +EC23 +Dorsomorphin+SANT1+ALK5iII +ILV. Day 15–17: EC23+Dorsomorphin +SANT1+ALK5iII+Exendin-4. Day 18–23: BMP4+FGF2+HGF+IGF+Nicotinamide+Forskolin+Exendin-4+ALK5iII | >80% SOX17+; >68% FOXA2+ | 92% PDX1+ | NA | 34% C-peptide+ | √ | In vitro √; In vivo √ | [24] |
hiPSCs | Day 1–3: Activin-A+CHIR. Day 4–6: KGF. Day 7–8: KGF+RA+SANT1+Y27632+LDN+PdbU. Day 9–13: KGF+RA+SANT1 +Y27632+Activin A. Day 14–20: RA+SANT1+T3+XXI+ALK5i+Heparin+Betacellulin. Day 21–34: T3+ALK5i+ CMRL supplemented | NA | NA | 52-89% NKX6.1+/PDX1+ | 30% NKX6.1+/C-peptide+ | √ | In vitro √; In vivo √ | [43] |
BM-MSCs | Day 1–2: β-ME. Day 3–10: NEAA+bFGF+EGF+2% B27+L-glutamine. Day 11–18: Betacellulin+Activin-A+2% B27+Nicotinamide. | NA | NA | NA | 5–10% INS+/C- peptide+ | √ | In vitro √; In vivo √ | [44] |
ASCs | Day 1–3: Activin-A+Sodium butyrate+ITS+β-ME. Day 4–5: Taurine+ITS. Day 6–10: Taurine+ITS+Nicotinamide+NEAA+GLP-1. | 28% SOX17+; 22% FOXA2+ | 65% PDX1+ | 48% C-peptide+ | √ | In vitro √; In vivo √ | [45] | |
hMSCs | Day 1–7: Nicotinamide. Day 8–14: Exendin-4 | NA | NA | NA | 15% INS+ 6% C-peptide+ | √ | In vitro √; In vivo √ | [46] |
Stage | Transcriptional Factors | Function |
---|---|---|
DE | SRY-related HMG-box 17 | Regulation of embryonic development |
Forkheadbox A2 (HNF-3β) | Endodermal marker, differentiation of pancreas | |
C-X-C chemokine receptor type 4 | Chemokine signals in early pancreatic differentiation | |
Cerberus | Endodermal marker, differentiation of pancreas | |
Transcription factor GATA-4 | Regulates the development of endoderm-derived organs | |
Brachyury protein | Brachyury is an important factor in promoting theepithelial-mesenchymal transition | |
Orthodenticle homeobox 2 | Influences proliferation and differentiation | |
Homeobox protein goosecoid | Cell-fate specification | |
Receptor tyrosine kinase | Involved in intracellular signaling | |
Mix paired-like homeobox | Plays a role in proper axial mesendoderm morphogenesis and endoderm formation | |
Hepatocyte nuclear factor 4 α | Controls the expression of the FOXA2 and SOX17 genes | |
PGT | Pancreatic and duodenal homeobox | Early pancreatic development, α- and β-cell, and exocrine tissue genesis, important activator of insulin |
Transcription factor SOX-9 | Regulates epithelial progenitor expansion and endocrine differentiation | |
Hepatocyte nuclear factor 1 homeobox B | Plays a crucial role in early development | |
PE | NK6 TF related locus 6 | Final differentiation of β-cells |
Homeobox protein CDX-2 | Tumor suppressor in pancreas | |
Sex determining region Y | Essential for maintaining self-renewal and pluripotency | |
Motor neuron and pancreas homeobox 1 | Regulation of β-cell development | |
PPs | NK2 TF related locus 2 | Pancreatic endocrine development and differentiation into pancreatic β-cells |
Neurogenin 3 | Formation of pancreatic endocrine precursors, differentiation of pancreatic precursor cells towards endocrine lineage | |
Neurogenic differentiation | Differentiation and islet growth, endocrine differentiation in pancreatic progenitors | |
Paired box gene 6 | Formation of α-cells, activates glucagon transcription | |
Paired box gene 4 | Formation of β-cells and δ-cells, repress glucagon transcription | |
Hepatocyte nuclear factor 6 | Essential for endocrine differentiation | |
Islet 1 | Early endocrine cell differentiation | |
Pancreas associated transcription factor 1 | Stage-specific roles during pancreatic organogenesis | |
EPs | Avian musculoaponeurotic fibrosarcoma oncogene family A | Formation of α- and β-cells, activates genes involved on mature endocrine functions like glucose sensing, vesicle maturation, calcium signaling, and insulin secretion |
Avian musculoaponeurotic fibrosarcoma oncogene family B | Controls and activates insulin gene expression | |
Chromogranin A | Maintains islet volume, cellular composition, and function | |
Insulin | Pancreatic β-cell maturation | |
Glucagon | Produced by pancreatic α -cells, leads to increased gluconeogenesis | |
Somatostatin | Regulates the endocrine system | |
Ghrelin | Regulates homeostasis | |
Pancreatic polypeptide | Metabolic homeostasis |
Small Molecules | Function | Application | Stem Cell Sources | References |
---|---|---|---|---|
IDE1/2 | Activator of TGF-β pathway | Induces DE formation | hPSCs | [59,60] |
NECA | Adenosine receptor agonist | Promotes β-cell proliferation | Fibroblasts | [41] |
Dexamethasone | Agonist of glucocorticoid receptor | Enhances β-cell proliferation | hESCs, hiPSCs | [19,61] |
ALK5iII | ALK5 inhibitor | Promotes β-cell differentiation and maturation | hESCs, hiPSCs | [15,17,19,41,61,62,63] |
Taurine | Alter membrane potential and have an effect on ion currents | Secretion of insulin | hESCs | [40] |
SCG (sodium cromoglicate) | Anti-inflammatory | Facilitates the differentiation of PDX1-positive cells into INS-positive cells | hESCs, hiPSCs | [64] |
N-acetyl cysteine | Antioxidant | Improves insulin production and secretion | hESCs | [41,63] |
Forskolin | AXL inhibitor/ cAMP signaling activator(an activator of adenylyl cyclase) | Promotes β-cell formation | hESCs, hiPSCs | [19,41,61,62] |
Noggin | BMP inhibitor | Suppresses hepatic lineage differentiation | hESCs, hiPSCs | [15,18,19,40,59,61,65,66] |
Dorsomorphin | Suppresses hepatic lineage differentiation | hESCs, hiPSCs | [19,22,61] | |
LDN | Promotes pancreatic specification | hESCs | [15,17,25,62,67] | |
Vit C | Cofactor of epigenetic modulators | Enhances reprogramming efficiency and promotes pancreatic specification | hESCs | [23,62] |
RG | DNA methylase inhibitor | Epigenetic modulators | Fibroblasts | [41] |
Betacellulin | EGF | Growth and differentiation of β-cells | hESCs, hiPSCs | [17] |
DAPT | Gamma secretase inhibitor | Block notch signaling/support long term self- renewal | hESCs, hiPSCs | [22] |
CHIR99021 | GSK-3β inhibitor | Induces DE formation | hPSCs, hiPSCs | [17,19,22,25,59,61,62,67,68] |
Par | Histone demethylase inhibitor | Epigenetic modulators | Fibroblasts | [55] |
Sodium Butyrate | Inhibitor of histone deacetylation | Activates genes of early pancreatic development | hMSCs, hESCs, ASCs | [40,69] |
Stauprimide | Inhibitor of NME | Destabilizes c-myc pluripotency marker | ESCs | [70,71] |
Db-cAMP | Nerve growth factor | Increases insulin secretion by increasing mRNA | hESCs, hiPSCs | [22] |
Exendin-4 | Peptide analog of GLP1 | Improves glucose tolerance by increasing insulin secretion | hESCs, hiPSCs | [22,40,62,72] |
Wortmannin | PI3K inhibitor | Enhances yield of DE cells | hPSCs | [61,73] |
ILV | PKC activator | Promotes PDX-positive cells | hESCs, hiPSCs | [39,59,74] |
PdBU | Promotes pancreatic differentiation | hESCs, hiPSCs | [17,25,67] | |
TPB | Promotes pancreatic specification | hESCs | [15,41,59] | |
Resveratrol | Polyphenolic compound | Up-regulation of key genes for β-cell function | hESCs | [75] |
Fasudil | ROCK1 inhibitor | Directs pancreatic lineage differentiation | ESCs | [30] |
RKI-1447 | Directs pancreatic lineage differentiation | ESCs | [30] | |
Thiazovivin | Directs pancreatic lineage differentiation | ESCs | [30] | |
Y27632 | Pancreatic differentiation | hESCs, hiPSCs | [25,67] | |
CYC | SHH inhibitor | Promotes pancreatic lineage | hESCs, hiPSCs | [22,59,62,72,75] |
SANT-1 | Promotes pancreatic specification | hESCs, hiPSCs | [17,19,30,41] | |
SB171542 | TGF-β type 1 receptor inhibitor | Induces NGN3 expression | hESCs, hiPSCs | [19,22,59,62] |
T3 | Thyroid hormone | Promotes β-cell differentiation and maturation | hESCs | [17,41,63] |
Nicotinamide | Vitamin | Promotes generation of progenitors | hESCs, hiPSCs | [22,61] |
PathologicalCondition | Enrolled Patients | Intervention | National Clinical Trial Number | Outcome Measures | Phase | Status |
---|---|---|---|---|---|---|
Autologous mesenchymal stromal cell | 24 | Autologous mesenchymal stromal cell | NCT02384018 | C-peptide level, liver function, kidney function, absence of severe hypoglycemic episodes | Phase 1 | Ongoing |
T2DM With Renal Manifestations | 54 | Human umbilical cord mesenchymal stem cells | NCT04216849 | Estimated glomerular filtration rate, urinary albumin creatinine ratio | Phase 2 | Ongoing |
Diabetic Nephropathy | 15 | Human umbilical cord mesenchymal stem cells | NCT04125329 | Incidence of treatment-emergent, treatment-chronic adverse events and estimated glomerular filtration rate | Early Phase 1 | Ongoing |
Diabetic Nephropathies | 20 | Wharton Jelly Mesenchymal stem cells | NCT03288571 | Incidence of treatment-emergent adverse events, glomerular filtration rate, and protein to creatinine ratio | Phase 2 | Ongoing |
Diabetic Kidney Disease | 48 | Mesenchymal Stromal Cells | NCT02585622 | Adverse events, glomerular filtration rate, urinary albumin/creatinine ratio, urinary albumin excretion, fasting blood glucose, and fasting blood glucose | Phase 2 | Ongoing |
T1DM | 20 | Intravenous Injection of autologous mesenchymal stem cells | NCT04078308 | Baseline fasting blood sugar (FBS), assessing fasting blood sugar (FBS), C-peptide concentration, and Insulin uptake | Phase 2 | Ongoing |
T2DM | 30 | Expanded autologous bone marrow-derived mesenchymal stem cell | NCT03343782 | Insulin dose, adverse events, and hemoglobin A1c (HbA1c) level | Phase 2 | Completed |
T1DM | 20 | Mesenchymal stem cells | NCT01068951 | C-peptide concentration | NA | Completed |
T2DM | 200 | Umbilical cord mesenchymal stem cells | NCT02302599 | Change from baseline in fasting glucose over time | Phase 1 | Completed |
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Thakur, G.; Lee, H.-J.; Jeon, R.-H.; Lee, S.-L.; Rho, G.-J. Small Molecule-Induced Pancreatic β-Like Cell Development: Mechanistic Approaches and Available Strategies. Int. J. Mol. Sci. 2020, 21, 2388. https://doi.org/10.3390/ijms21072388
Thakur G, Lee H-J, Jeon R-H, Lee S-L, Rho G-J. Small Molecule-Induced Pancreatic β-Like Cell Development: Mechanistic Approaches and Available Strategies. International Journal of Molecular Sciences. 2020; 21(7):2388. https://doi.org/10.3390/ijms21072388
Chicago/Turabian StyleThakur, Gitika, Hyeon-Jeong Lee, Ryoung-Hoon Jeon, Sung-Lim Lee, and Gyu-Jin Rho. 2020. "Small Molecule-Induced Pancreatic β-Like Cell Development: Mechanistic Approaches and Available Strategies" International Journal of Molecular Sciences 21, no. 7: 2388. https://doi.org/10.3390/ijms21072388