Several cytokines/growth factors are involved in the precise and directional development of specific tissues and organs. In the craniomaxillofacial region, the development of teeth depends largely on the orderly interaction between the ectodermal epithelium and the mesenchyme [1].

The tooth development process is generally divided into the initiation stage, the bud stage, the cap stage and the bell stage (Fig. 1). At the initiation stage, the epithelial tissue known as the dental placode, locally thickens, and continues to develop into the tooth bud [2]. Meanwhile, the mesenchymal tissue near the tooth bud, aggregates to form the tooth germ. Through the proliferation and folding of the epithelial tissue, the buds gradually evolve to the cap and bell stages. Clusters of undifferentiated epithelial cells, known as the enamel knot, can be observed at the center of the inner enamel epithelium. Each tooth germ has only one primary enamel knot. When the primary enamel knot disappears, secondary enamel knots will appear at the prospective apex of the molars. The enamel knot is considered to be the signal center that controls the shape of the cusp [3]. Subsequently, the epithelial tissue forms odontoblasts and ameloblasts, that lead to the formation of the dentin and the enamel, respectively. After the crown formation, the cervical loop of the dental epithelial cells, continues to elongate and forms a double-layered epithelial structure, found between the dental follicle and the dental papilla, and named the Hertwig’s epithelial root sheath (HERS). Conventionally, researchers believe that HERS is the signal center of the root formation [4].

Fig. 1
figure 1

Spatial-temporal expression of developmental signal molecules during tooth development. Tooth morphogenesis is divided into the initiation, bud, cap and bell stages. Expression of the fundamental signal molecules in the epithelium and mesenchyme are shown and corresponding to each stage

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Many studies have shown that cytokines/growth factors such as BMPs, FGFs, SHHs, WNTs and TNFs, play an important role during this process [1]. Moreover, the expression of these cytokines is characterized by a spatial-temporal specificity [5,6,7] (Fig. 1). Aberrant expression may lead to tooth development abnormalities [1]. The spatio-temporal control of the developmental cues might be the future for tooth regeneration applications.

With advances in developmental biology and drug delivery, tooth regeneration would be more promising than ever before (Fig. 2). In the following sections, we summarize recent advances in developmental biology and discuss the clues for tooth regeneration in the context of the spatial-temporal control of bioactive drug release.

Fig. 2
figure 2

Schematic representation of the bio-inspired dental regeneration strategy. The gene expression pattern during tooth development is obtained by biology and bioinformatics, and the development associated with spatial-temporal specific expression could be approached by using different control release strategies for regeneration purpose, and making the goal of tooth regeneration expectable

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Cytokines/ Growth Factors and Tooth Development

BMP, FGF, WNT and SHH signaling pathways are known signaling pathways in tooth development (Tables 1 and 2). Recently, other signaling pathways, such as TNF [8], YAP-Hippo [9] and mTORC1 [35]. It is also expressed in the surrounding inner enamel epithelium and in the stratum intermedium cells during the following stages [36]. The decrease or loss of SHH expression leads to a cap stage tooth rudiment, which has a severely disrupted morphology [37]. SHH also plays vital roles in the development of periodontal tissue [38]. As described above, BMP, WNT and SHH signals are interconnected during tooth development. The differential fate of epithelial stem cells, in mouse molars and incisors, is defined by BMP/SHH signaling network [39]. When reducing SHH function in the epithelium, WNT and FGF signaling are upregulated [40].

Other Factors

The EDA (ectodysplasin A)-EDAR (ectodysplasin A receptor) system has also been found to be involved in tooth development. It regulates interactions within or between epithelial and mesenchymal cells, and tissues functions by controlling NF-κB-mediated transcription of effectors or inhibitors of the WNT, SHH, FGF and TGF-β pathways [41]. Mutation in Tabby and identified as Ectodysplasin A1 (EDAA1), displays a characterized tooth phenotype, associated with significant reduction in the size and number of molar cusps, and frequent absence of incisors and third molar in the studied mice [42]. Another recent study suggested that EDA mutations cause non-syndromic tooth agenesis [43].

Dental Regeneration Via Reactivating the Developmental Cues

Dental regeneration medicine represents an attractive multidisciplinary approach that offsets traditional dental restoration techniques. As mentioned above, a variety of cytokines participate in different stages of tooth development and in a spatial-temporal manner [1]. The control release of the cytokines for dental regeneration is appealing and is being implemented. Its development depends on research progress in biomaterials, stem cell biology and in other scientific technologies (Fig. 3).

Fig. 3
figure 3

Strategies for tooth regeneration by reactivating developmental cues. A Different control release strategies of secretory factors based on biological materials. a) Self-degradation; b) pH-responsive release; c) Magnetic release; d) Thermal release; e) 3D printing. B Small RNAs are involved in different parts of the gene expression process. C Different turn-on/off systems for spatial-temporal control of gene expression. D In vivo delivery of gene expression system. E Transplantation of genetically modified cells. FUnder the above strategies, cells from different sources can be directed to differentiate into specific cells and eventually achieve tooth regeneration

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Control Release of Secretory Factors

Biomaterial Based Control of Secretory Factors Releases

Self-degradation is based on the rate of materials degradation in a specific physiological environment, to achieve the spatial-temporal sustained release of cytokines (Fig. 3A a). Although this technique has been widely used in tissue engineering scaffolds, traditional techniques have significant drawbacks, such as high initial release and low bioactive molecular activity. In order to inhibited the burst release of cytokines and enhanced structural stability, many scholars are committed to inventing various kinds of better materials. Fahmy and his co-workers used a low dose of rBMP2 loaded on a resorbable bioactive ceramic to accelerated bone regeneration [44]. Recently, chirality-controlled enzyme-responsive protein nanocapsules were shown to alter the degradation rate by changing the constituent ratio of the material composition, resulting in enhancing wound healing and tissue repair in vivo via the delivery of multiple proteins in a spatiotemporal manner [45]. Affinity interaction is an alternative strategy to achieve sustained release of cytokines. In tissue engineering, the most common way to improve the release kinetics is through heparin-immobilized scaffolds that immobilize cytokines [46]. Wu et al. showed that heparin-based coacervate of FGF2 played a synergistic role with cell proliferation and endogenous facilitated VEGF in improving skin wound healing [3A e) [59]. The flexibility and controllability of 3D bioprinting enable complex and customized release profiles of multiple cytokines to achieve spatial-temporal gradients that regulate cellular functions in tissue or organ regeneration [60, 61]. Moreover, many studies have promoted the application of 3D printing technology in cytokine sustained-release by improving processing [62], advancing technology [63] or allowing combinations with other forms of carriers [64]. Up to now, these materials have been successfully used in various tissue and organ regeneration experiments in vitro and in vivo, such as vascular regeneration [65], bone regeneration [63] and skin regeneration [66]. The 4D printing technology is a dynamic and time dependent manufacturing process based on advanced 3D-print features, which providing great potential for tissue and organ engineering applications [67].

Control Delivery of Small RNAs

Small RNAs including small interfering RNAs (siRNAs) and microRNAs (miRNAs), are part of the short chain RNAs in non-coding RNAs (ncRNAs) (Fig. 3B). SiRNAs are double-stranded RNAs that downregulate gene expression guided by sequence complementarity with the target mRNA. Since its first discovery in 1998 [68], its delivery strategy has developed rapidly. So far, many different siRNA delivery approaches including siRNA conjugates and lipid nanoparticles, have been applied to disease treatment and tissue regeneration [69]. For example, Zhang et al. developed a targeting system for delivering siRNAs to markedly promoted bone formation [70]. More recently, Castleberry et al. developed an ultrathin polymer coating to sustain the local delivery of siRNA so as to improve wound healing in diabetic mice [71]. Furthermore, the potential toxicities of these technology have been gradually discovered. These include but not limited to on-target effects, sequence-specific off-target effects, immune activation and toxicity associated with the delivery vehicles [72].

MiRNAs can simultaneously identify hundreds of target mRNAs with multiple miRNAs working together for the same mRNA [73]. A As post-transcriptional gene regulators, they can target and disassemble mRNAs or repress their translation [74]. Many studies have shown that miRNAs play a significant regulatory role in tissue repair and regeneration, such as wound healing [75], cardiac repair [76]. In vivo delivery of exogenous miRNAs provides an effective way to regulate gene expression during tissue repair and regeneration, which was proved and validated in mice [77] and zebrafishs [78]. To optimize miRNA delivery, Zhang et al. developed a cell-free 3D scaffold with biodegradable microspheres, that spatially regulated the release of miR-26a to repair critically-sized bone defects in osteoporotic mice [79]. Zhou et al. used miR-126-loaded electrospun membranes for miRNAs local delivery to improve blood vessel regeneration [80]. Moreover, a recent study showed that intracardiac injection of a single administration of synthetic miRNA-lipid formulations enhanced cardiac repair in mice after myocardial infarction [81].

Spatial-Temporal Delivery of Gene Expression Systems

Delivery of gene expression systems that produce locally nascent proteins in vivo, is more advantageous compared to traditional methods for products delivery. In recent years, research on genes-controlled expression has rapidly developed. Some important and potential technologies will briefly be introduced below, and their combinations will also be discussed (Figure C-D).

Spatial-Temporal Control of Gene Expression

Hormone Induction

All kinds of hormones participate in development and regeneration stages. Steroid hormones function by binding to receptor proteins in the cytoplasm of target cells to form hormone-receptor complexes, which enter the nucleus and bind to specific chromosomal sites to regulate the transcription of specific genes. For example, estrogens play pivotal roles in various physiological processes, most of which are mediated by the estrogen receptors alpha (ERα), beta (ERβ) and G protein-coupled receptor 30 (GPR30). Many studies have used estrogen-inducible promoters to modify gene expression systems to regular gene expression [82,83,84]. Senturk et al. optimized a CRISPR/Cas9 system by combining it with an FKBP12-derived destabilizing domain and an inducible Cre-estrogen receptor fusion domain, which enabled rapid and tunable gene editing [85].

Optogenetics Regulation

Optogenetics is a rapidly develo** bioengineering technology which integrates many subjects, such as optics, software control technology, genetic engineering technology, electrophysiological technology. It was originally applied in the field of neurology and a recent review indicated that it could control nerve growth and neurotrophic factor expression in a precise spatial and temporal manner [86]. The light-based mechanisms can activate or inhibit the expression of target genes in the FGF [87], WNT/β-catenin [88] and TGF-β signaling pathways [89] by light-induced conformational change of various photoactivatable proteins or photocaging/uncaging of effectors [90]. Yang et al. created the LightON system, a light-switchable transgene system, which can initiate spatiotemporal expressions of target transgenes in mammalian cells, upon light stimulation [91]. However, potential toxicity associated with the high expression was reported by a study of zebrafish embryogenesis, which may limited its application [92]. To overcome this obstacle, the blue-light activated EL222 system, renamed TAEL was invented, and which drived the expression with minimal toxicity [93, 94]. In addition, some studies have used optical gene elements to link Cre recombinase to regulate DNA recombination [95, 96]. Recently, Nguyen et al. combined genetically encoded photo-switchable calcium actuators with dCas9 to control gene expression, overcoming some limitations of the CRISPR/Cas9 (dCas9) system [97]. Simultaneously, a CRISPR-dCas9 effector device that is activated by far-red light (FRL), engineered by Shao and his research team, efficiently promoted the differentiation of induced pluripotent stem cells (iPSCs) into functional neurons by up-regulating NEUROG2, a single neural transcription factor [98].

Dental Development-Related Specific Promoters

In the process of tooth development, some site-specific promoters like WNT1 promoter, play a vital role in regulating the orderly expression of genes. WNT1 encodes the signaling protein WNT1, involved in the canonical WNT pathway. Previous research has shown that the expression of WNT1 is restricted to the migrating neural crest cells, which contribute to tooth and mandible development [99]. Simultaneously, Chai et al. successfully constructed a transgenic model under the control of the WNT1 promoter [99]. Up to now, this conditional knockout model of transgenic mice has been widely used in the study of tooth development and regeneration [100,101,102].

In addition, dentin matrix protein 1 (DMP1) produced by odontoblasts and osteoblasts is mainly expressed in bone and dentin [103]. Jacob et al. showed that TCF11, which could specifically bind to the DMP1 promoter, played a significant role in regulating the transcription of DMP1 in odontoblasts and osteoblasts [103]. This provides a way to spatiotemporally regulate the expression of DMP1.

In Vivo Delivery of Gene Expression System

The in vivo gene delivery strategy can be generally divided into viral and non-viral vector delivery systems (Fig. 4). Viral vectors including oncoretroviruses, lentiviruses (LVs), adenoviruses (AVs) and adeno-associated viruses (AAVs), have relatively high efficiency. Initially, they are widely used in changing the expression of specific genes in vivo and in vitro [104]. In contrast to LVs, the nonintegrated DNA delivered by AAVs would be diluted during mitosis because of lack of integration machinery. However, it could be stably maintained in a nonintegrated form to mediate persistent gene expression in predominantly postmitotic cells [104]. With regard to damage repair and tissue regeneration, Eggers et al. used a lentiviral vector to regulate controlled expression of glial cell-line derived neurotrophic factor (GDNF), which exerts multiple effects on both Schwann cells and axons in the injured peripheral nerve [105]. Moreover, adenovirus-mediated WNT10b overexpression promoted hair follicle regeneration via the activation of the canonical WNT signaling pathway [

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Acknowledgements

Funding: This work was supported by grants from National Key R&D Program of China (2016YFC20160905200), National Natural Science Foundation of China (81600824), Natural Science Foundation of Guangdong Province (2016A030310220, 2018A030310278), Young Teachers Training Program of Sun Yat-sen University (16ykpy46, 17ykpy73), Science and Technology Program of Guangzhou (201707010106, 201804010459) and the Young Elite Scientist Sponsorship Program by CAST (2016QNRC001).

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  1. Guanghua School of Stomatology, Hospital of Stomatology, and Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China

    Delan Huang, Jianhan Ren, Runze Li, Chenyu Guan, Zhicai Feng, Baicheng Bao, Weicai Wang & Chen Zhou

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  1. Delan Huang
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  8. Chen Zhou
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DH was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

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Huang, D., Ren, J., Li, R. et al. Tooth Regeneration: Insights from Tooth Development and Spatial-Temporal Control of Bioactive Drug Release. Stem Cell Rev and Rep 16, 41–55 (2020). https://doi.org/10.1007/s12015-019-09940-0

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