Priming strategies for controlling stem cell fate: Applications and challenges in dental tissue regeneration

Table 1 Priming strategies for controlling mesenchymal stromal cell fate

Priming strategies		Cell type	Benefits	Mechanisms	Reference
	Hypoxia:
	1%–3% O2	DPSCs; PDLSCs	Improve survival	Upregulation of stem cell markers; Regulation of metabolic activities; Activation of the p38/MAPK and ERK/MAPK pathways	[66,67,70]
		DPSCs; SHEDs; SCAPs	Promote angiogenesis	Increase proangiogenic factors releasing	[60,62,63]
Culture conditions		DPSCs; SCAPs; PDLSCs	Enhance differentiation potential	Upregulation of odontoblastic markers	[68,69,71,72]
		PDLSCs	Enhance anti-inflammation effect	Upregulation of IL-37	[73]
	Pharmacological stimulation	DPSCs	Promote angiogenesis	Increase intracellular levels of HIF-1α	[51,64,65]
		PDLSCs	Improve survival but inhibit differentiation potential		[49]
	3D culture:
	Single cell type	DPSCs; PDLSCs	Enhance differentiation potential	Upregulation of odontoblastic markers	[83,84,87]
	Coculture	DPSCs and ECs	Promote angiogenesis		[86]
	Mechanical and physical stimuli:
	LIPUS	DPSCs; PDLSCs	Increase proliferation	Activation of MAPK pathway	[94,95]
	Cyclic mechanical tension	DPSCs	Promote osteogenic differentiation; Increase cytokines release	Upregulation of osteoblastic markers	[98,99]
	Uniaxial stretch	DPSCs	Increase proliferation but inhibit osteo/odontogenic differentiation		[96,97]
	Cytokines
	SDF-1	DPSCs; PDLSCs	Promote cell migration	Activation of SDF-1/CXCR4 axis; Autophagy; Activation of AKT and GSK3β/β-catenin pathways	[104,107,109,110]
		PDLSCs	Anti-apoptosis	Activation of ERK pathway	[105]
		DPSCs; PDLSCs	Enhance differentiation potential	Upregulation of odontoblastic markers; Upregulation of osteoblastic markers	[106,108,111]
	TNF-α		Enhance immunomodulatory effects	Mediated by TNF/TNFR2 signaling	[124-126]
			Enhance osteogenic differentiation	Activation of p38 pathway; Activation of miR-21/STAT3 and NF-κB pathway	[127-129]
			Inhibit differentiation potential (50-100 ng/mL)	Activation Wnt/β-catenin pathway	[132]
	G-CSF; IFN-γ	DPSCs	Promote cell migration		[114,121,122]
		DPSCs	Enhance or inhibit differentiation potential depend on cytokines concentration		[116,120,121]
Preconditioning mediators	growth factors
	bFGF	DPSCs	Promote angiogenesis		[136,139-141]
		DPSCs; PDLSCs	Enhance differentiation potential on dose dependent (20-50 ng/mL in vitro; 15 μg/mL-5 mg/mL in vivo)	Upregulation of odontoblastic markers; Upregulation of osteoblastic markers; Upregulation of neural markers; Activation of FGFR/MEK/ERK1/2 and BMP/BMPR signaling pathways	[137,138,141,144,149-151]
		DPSCs	Promote anti-inflammation effect	Altered cytokines expression;	[146-148]
	IGF-1	PDLSCs	Promote cell survival		[165]
		DPSCs	Anti-apoptosis		[164]
		DPSCs; PDLSCs	Enhance differentiation potential	Upregulation of osteoblastic markers; Upregulation of odontoblastic markers; Activation of mTOR pathway; Target of EphrinB1	[160-162,166]
	Sox-2	DPSCs	Improve cell migration		[171]
	Bcl-2; Oct-4	DPSCs	Improve cell survival	Upregulation of stemness-rated genes;	[168,169]
Genetic modification	Foxo-1	PDLSCs	Promote anti-inflammation effect	Resistance to oxidative stress	[175]
	BMP family; Runx2	DPSCs; SCAP; DFCs	Enhanced differentiation potential	Upregulation of osteoblastic markers; Upregulation of odontoblastic markers	[178-184]

DPSCs: Dental pulp stem cells; PDLSCs: Periodontal ligament stem cells; SHED: Stem cells from human exfoliated deciduous teeth; SCAP: Stem cells from the apical papilla; LIPUS: Low-intensity pulsed ultrasound; SDF-1: Stromal cell-derived factor-1; TNF-α: Tumor necrosis factor-α; G-CSF: Granulocyte-colony stimulating factor; IFN-γ: Interferon-γ; bFGF: Basic fibroblast growth factor; IGF-1: Insulin-like growth factor-1; Bcl-2: B-cell lymphoma 2.