Dental mesenchymal stromal/stem cells in different microenvironments— implications in regenerative therapy

Table 1 Effects of different oxygen levels on regenerative potential of human dental mesenchymal stem cells

Hypoxia level	Outcome	Ref.
DPSCs
< 1% O2	Weak ALP activity, weak calcium deposition	Janjić et al[75], 2019
2% O2	Proliferation↑; odontogenic differentiation↑; angiogenesis↑; in vivo: Angiogenesis inside the pulp chamber↑, the formation of odontoblast-like cells lining along the dentin–pulp interface↑	Kuang et al[76], 2016
	No change in proliferation; calcium deposits↑; proteoglycan deposition↑; lipid droplets↑; PPAR𝛾2 mRNA↑	Zhou et al[71], 2014
	Proliferation↓; Runx2 mRNA expression↑ (both 2D and 3D conditions); Runx2 and Col1A mRNA expression, osteopontin in 2D culture↑, calcium deposition in 3D culture↑, calcium deposition in 2D culture↓	Labedz-Maslowska et al[73], 2020
3% O2	BMP2, OCN and RUNX2 protein expression↑; calcium deposits↑; RunX2 and Sp-7 mRNA expression↑; in vivo: In a mouse apical periodontitis bone destruction model, hDPSC recruitment and recovery of alveolar bone mass in infected periapical tissue↑, osteogenesis and bone mineralization↑	Wu et al[77], 2016
5% O2	Proliferation↑; mineralization↑	Kwon et al[63], 2017
PDLSCs
1.5%-2% O2	ALP activity↓; SPARC protein expression↓; ALP, OCN, and BMP-2 mRNA expression↓; proliferation↓	Hou et al[79], 2009
2% O2	Calcium deposition, proteoglycan deposition↑; lipid droplets↑; Runx2, Sox9 mRNA expression↑	Zhou et al[71], 2014
	ALP activity↑; Runx2 and Sp7 mRNA and protein expression↑; mineralization↑	Wu et al[80], 2013
	SPP1, RUNX2, SP7 mRNAs and protein expression↑	Li et al[65], 2014
	Proliferation↑; RUNX-2 and ALP protein expression↑; no effect on adipogenic differentiation; in vivo: Stronger bone regeneration region in male nude mice, more mineralized tissue in a periodontal defect model	Yu et al[64], 2016
	Proliferation↑; Runx2, osteopontin and osteocalcin mRNA expression↑; in vivo: After 12 wk of transplantation, hypoxia-treated cells differentiated into osteoblast-like cells that formed bone-like structures	Zhang et al[66], 2014
	ALP activity↑; Runx2 mRNA expression↑	Chen et al[81], 2017
3% O2	Proliferation↑; osteogenic and adipogenic differentiation↓; chondrogenic differentiation↑; preconditioning: Osteogenic and adipogenic differentiation↑	Murabayashi et al[72], 2017
	Runx2, Alp, Col1, and Ocn mRNA expression↑; RUNX2 protein ex vivo and in situ↑	Xu et al[82], 2019
5% O2	ALP activity↓	Matsuda et al[78], 1998
5% O2; 1% O2	Proliferation↓; ALP activity↑; Opn, Alp mRNA expression↑; Cemp1, Cap mRNA expression↑	Xiao et al[74], 2017
8% O2	Proliferation↑; Cemp1, Ocn mRNA expression↑; CEMP protein expression↑; mineral deposition↑; ALP activity↑; in vivo: CEMP1 protein expression in mouse PDL spaces↑	Choi et al[67], 2014
SHEDs
1% O2	Proliferation↑; mineralization↑; ALP activity↑; OPN and DMP1 protein expression↑; in vivo: After implantation in immunodeficient mice, the tissue-engineered constructs seeded with hypoxia primed SHED mediated faster intramembranous bone formation into critical size calvarial defects	Novais et al[69], 2019
2.3% O2	Proliferation↑; no effect on adipogenic and osteogenic differentiation	Kanafi et al[68], 2013
SCAPs
1% O2	No effect on proliferation; RunX2, Alp, TGF-1↑; neuronal differentiation (CNP, NSE, and SNAIL mRNA expression↑; angiogenesis (VEGF A and B)↑; adipocyte lipid binding protein (ALBP)↓	Vanacker et al[70], 2014
3% O2	ALP activity↑; mineralization↑; Dspp, Dmp1 and Bsp mRNA expression↑	Yang et al[83], 2020
Chemical hypoxia
DPSCs
100 μM CoCl2	No effect on proliferation; SOX9 and VCAN; no expression Col2a1, Acan↑, Col 10 mRNA expression↓; proteoglycans↓	Teti et al[85], 2018
100 mM CoCl2	Short term: RUNX2, ALP, OCN, COL1A1 mRNA and protein expression↑; long term: RUNX2, ALP, OCN, COL1A1 mRNA and protein expression↓	Zheng et al[89], 2021
	ALP activity↓; Alp, Ocn, and Runx2 mRNA expression↓; mineralization↓	Osathanon et al[86], 2014
200 μM CoCl2	ALP activity↓; Runx2, Alp, Ocn and Col-1 mRNA and protein expression↓; mineralization↓	Song et al[87], 2017
PDLCs
200 μM; 400 μM CoCl2	Proliferation↓; ALP, RUNX2, collagen I↓	Dong et al[88], 2014
1 mM DMOG	No effect on proliferation; COL1, RUNX2 and CEMP1 protein expression↑	Li et al[92], 2016
0, 5, 10, 20 μM deferoxamine	Proliferation↓; Runx2, Opn and Col1 mRNA expression↑; calcium deposition↑	Mu et al[91], 2017
SHED
50 or 100 μM CoCl2	ALP activity↓; calcium deposition↓; Alp, Runx2, and ColI mRNA expression↓	Chen et al[90], 2019

↑ and ↓ represent increasing or decreasing effect, respectively. ACAN: Aggrecan; ALBP: Adipocyte lipid binding protein; ALP: Alkaline phosphatase; BMP-2: Bone morphogenetic protein 2; BSP: Bone sialoprotein; CEMP 1: Cementum protein 1; COL-1: Collagen-1; DMOG: Dimethyloxalylglycine; DMP1: Dentin matrix protein 1; DPSCs: Dental pulp stem cells; DSPP: Dentin sialophosphoprotein; OCN: Osteocalcin; OPN: Osteopontin; PDLSCs: Periodontal ligament stem cells; PPAR𝛾2: Peroxisome proliferator-activated receptor gamma; RunX2: Runt-related transcription factor 2; SCAPs: Stem cells from the dental apical papilla; SHEDs: Stem cells from human exfoliated deciduous teeth; Sox-9: SRY-box transcription factor 9; Sp-7: Osterix; SPARC: Secreted protein acidic and rich in cysteine; TGF-β: Transforming growth factor-beta; VEGF: Vascular endothelial growth factor.