Table 6.
Mechanisms for 3D tissue regeneration
| Function | Involved signaling pathway | Cell-matrix interaction related with genes and proteins |
|---|---|---|
| Musculoskeletal system | ||
| Osteogenesis | BMP/TGFβ | Mesenchymal progenitors-BMP2-deficient mice [212], BMP4-deficient mice [213], BMP7-deficient mice [214] |
| Wnt | Primary osteoprogenitors in Axin2LacZ/LacZ mice-Wnt protein [215] Fracture callus tissues-PTH [216] Mesenchymal skeletal cells-peptide ligand with high affinity integrin (CRRETAWAC) [217] |
|
| Notch | MSCs-Notch ligand (Jag1) [218–220] | |
| Chondrogenesis | Wnt/β-catenin | Mesenchymal progenitors-ablation of β-catenin in mesenchymal condensations [221] Micromass of MSCs-protein kinase C inhibitor (PMA), p38 kinase inhibitor (SB203580) [222] |
| TGFβ/Smad | FSTL1 KO MSCs-exogenous recombinant FSTL1 [223] Chondrocytes-Adamtsl2 KO growth plate [224] |
|
| BMP | MSC pellets-BMP inhibitor (dorsomorphin) [225] | |
| BMP/TGFβ | hACs and hMSCs-BMP-2, TGFβ1 [226] SDSCs-BMP-2, TGFβ1 (dexamethasone absent) [227] |
|
| IHH | Chondrocytes-PPR−/− wild-type chimeric mice vs. Ihh−/−PPR−/− wild-type chimeric mice [228] BMSCs-IHH, SHH [229] |
|
| Skeletal myogenesis | Wnt | Adult muscle stem cells-combining APC and β-catenin siRNAs [230] Satellite cells-Islr cKO mice [231] |
| Wnt/IGF | Satellite cell-like reserve myoblasts-GSK-3 inhibitor (LiCl or SB216763), insulin [232] | |
| Notch | Adult muscle stem cells-COLV depleted mice (compound Tg: Pax7-CreERT2; Col5a1flox/flox; R26mTmG(Col5a1 cKO)), CALCR ligand (Elcatonin) injection [233] Satellite cells-Syndecan-3 ablation [234] |
|
| Nervous system | ||
| Neurogenesis in CNC | PI3K/AKT/mTOR | Cerebral organoids-mTOR activators (INSR, ITGB8, IFNAR1) and repressors (PTEN) [235] |
| Notch | Neuronal progenitor cells-NOTCH2NL [236] hSpS spheroids-Notch inhibitor (DAPT) [237] |
|
| Wnt/FGF | mESCs-FGF/Wnt agonist (CHIR)/RA [238] | |
| TGFβ/Shh/Wnt | Astrocytes-TGFβ, Shh, and Wnt activators [239] | |
| Neurogenesis in PNS | c-Myc-TERT | Sensory axon-p53 inhibitor (PFTα), p53 activator (Tenovin-6) [240] |
| Circulatory system | ||
| Cardiomyogenesis | Wnt | Cardiac organoids-Wnt agonist (CHIR) [241–243], WNT inhibitor (IWP2) [243] |
| TGFβ | Cardiac organoids-TGFβ receptor inhibitor (e.g., SB431542) or overexpression of TGFβ receptor negative form [244,245] | |
| BMP | NKX2–5+CD31+ endocardial-like cells from hPSCs-BMP4, CHIR/BMP10, VEGF/BMP10 [246] | |
| Angiogenesis | Notch | Vascular organoids-Notch inhibitor (DAPT), Notch ligands (Dll4, Notch3) [247] |
| Wnt/VEGF-A | hPSCs aggregates-3D collagen I-matrigel gel driven by Wnt agonist (CHIR), BMP-4, VEGF-A, FGF-2 subsequently [248] | |
| Digestive system | ||
| Stomach tissue reconstruction | Wnt | Lgr5+ stem cells-matrigel containing Wnt activator (R-spondin1), Wnt3A [249] |
| Axin2+/Lgr5− stem cells-Wnt activator (R-spondin3) [250] | ||
| Intestine tissue reconstruction | Wnt | Lgr5+ ISCs-Wnt activator (R-spondin1), Wnt ligands [251–253] |
| Wnt/Notch | Lgr5+ ISCs-Wnt inhibitor (IWP-2)/Lgr5+ ISCs-Notch inhibitor (DAPT) [254] | |
| Notch | ISCs-Notch ligands driven by transient Yap1 activation [255] | |
| Hepatogenesis | Wnt | Lgr5+ stem cells-matrigel containing EGF, Wnt activator (R-spondin1) [256] Lgr5+ stem cells-HGF/Wnt activator (R-spondin1) [257] |
| Hedgehog | Hepatocytes and ductular cells-Hh ligands [258] Stellate cells-JNK1 [259] |
|
| Urinary system | ||
| Nephrogenesis | Wnt | Lgr5+ stem cells-Wnt receptor (Lgr5) [260] hPSCs-Wnt agonist (CHIR), Wnt inhibitor (DAPT) [261] |
| Wnt, FGF | hPSCs-Wnt agonist (CHIR), FGF9 [262,263] | |
| Urothelium regeneration | Hedgehog/Wnt | Stromal cells and epithelial cells in bladder-Shh-blocking antibody/stromal cells and epithelial cells-inactivation of essential component of Wnt pathway (Ctnnb1) [264] |
| Hedgehog | Long-term bladder organoids-smoothened agonist (SAG), Hh inhibitor (vismodegib), genetic manipulation [265] | |
| Wnt/Notch | Urothelial organoids-Wnt agonist (CHIR)/urothelial organoids-Notch inhibitor (DBZ) [266] | |
| Reproductive system | ||
| Fallopian tube and oviduct tissue reconstruction | Wnt/Notch | Fallopian tube organoids-Wnt modulators (Wnt3a, R-spondin1, EGF, FGF10), TGFβ inhibitor (ALK4/5), BMP inhibitor (Noggin)/fallopian tube organoids-Notch inhibitor (DBZ) [267] |
| Fallopian tube organoids-Wnt antagonist (PKF118–310)/fallopian tube organoids-Notch inhibitor (DBZ) [268] | ||
| Endometrium | Wnt | Endometrial organoids-Wnt activator (R-spondin1), Wnt inhibitor (IWP2), WNT3A, WNT7A, EGF, Noggin [269] |
| Endometrial organoids-WNT3A, Wnt activator (R-spondin1), EGF, Noggin [270] | ||
| Vagina tissue reconstruction | Wnt | Vaginal organoids-EGF, TGFb/Alk inhibitor (A83-01), ROCK inhibitor (Y-27632), PALL Corporation (Ultraserum-G) [271] |
| Prostate tissue reconstruction | Notch | Prostate organoids-Notch inhibitor (DAPT) [272] |
hAC, human articular chondrocyte; hMSC, human mesenchymal stem cell; SDSC, synovial-derived stem cell; IHH, Indian Hedgehog; PPR, PTH/PTHrP receptor; BMSC, bone marrow-derived mesenchymal stem cell; CNS, central nervous system; PNS, peripheral nervous system; hSpS, hindbrain/cervical spinal cord; mESC, mouse embryonic stem cell; ISC, intestinal stem cell;Hh, Hedgehog; hPSC, human pluripotent stem cell.