Stem cell-based bone and dental regeneration: a view of microenvironmental modulation

Abstract

In modern medicine, bone and dental loss and defects are common and widespread morbidities, for which regenerative therapy has shown great promise. Mesenchymal stem cells, obtained from various sources and playing an essential role in organ development and postnatal repair, have exhibited enormous potential for regenerating bone and dental tissue. Currently, mesenchymal stem cells (MSCs)-based bone and dental regeneration mainly includes two strategies: the rescue or mobilization of endogenous MSCs and the application of exogenous MSCs in cytotherapy or tissue engineering. Nevertheless, the efficacy of MSC-based regeneration is not always fulfilled, especially in diseased microenvironments. Specifically, the diseased microenvironment not only impairs the regenerative potential of resident MSCs but also controls the therapeutic efficacy of exogenous MSCs, both as donors and recipients. Accordingly, approaches targeting a diseased microenvironment have been established, including improving the diseased niche to restore endogenous MSCs, enhancing MSC resistance to a diseased microenvironment and renormalizing the microenvironment to guarantee MSC-mediated therapies. Moreover, the application of extracellular vesicles (EVs) as cell-free therapy has emerged as a promising therapeutic strategy. In this review, we summarize current knowledge regarding the tactics of MSC-based bone and dental regeneration and the decisive role of the microenvironment, emphasizing the therapeutic potential of microenvironment-targeting strategies in bone and dental regenerative medicine.

Fig. 1

Stem cell populations derived from different dental tissues/regions that constitute appealing MSC sources for bone and dental regeneration. DFCs, stem cells from dental follicle; SHED, stem cells from human exfoliated deciduous teeth; DPSCs, stem cells from dental pulp; PDLSCs, stem cells from PDL; SCAP, stem cells from the apical papilla

Fig. 2

Stem cell-based regenerative strategies for bone and dental tissue. Based on the cellular sources, stem cell-based bone and dental regeneration mainly includes two categories: endogenous stem cell- and exogenous stem cell-mediated regeneration strategies. Both resident and migratory endogenous stem cells have shown great potential in healing of bone and dental loss and defects. Alternatively, the application of exogenous stem cells is promising for regenerating bone and dental tissue through either cytotherapy via systemic/locoregional infusion or tissue engineering, including cell sheet, cell aggregate and scaffold-based tissue construction

Fig. 3

Microenvironmental impact on stem cells in bone and dental regeneration. Under pathologic microenvironmental conditions, the survival and functions of endogenous stem cells are impaired, as shown by declined self-renewal ability and disturbed differentiation potential, leading to development of bone diseases and declined regeneration ability. On the other hand, the therapeutic efficacy of transplanted exogenous MSCs are compromised by the diseased microenvironments of the donors where they are harvested and of the recipients where they are applied due to the impairment of stemness and immune modulatory function

Fig. 4

Stem cell-based bone and dental regeneration: a view of microenvironmental modulation. Diseased microenvironments, such as hormonal disorders, hyperglycaemia and inflammation, severely impair the therapeutic efficacy of both endogenous and exogenous stem cell-based regeneration of bone and dental tissue. Accordingly, microenvironmental therapeutics, including improvement of the endogenous niche, selection and modification of donor stem cells, and restoration of recipient microenvironment, have shown great promises in optimizing stem cell-based bone and dental regeneration. Furthermore, extracellular vesicles are emerging as promising cell-free strategies for bone and dental regeneration