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Background  The spatiotemporal regulation of essential genes is crucial for controlling the growth and differentiation of cells in a precise manner during regeneration. Recently, optogenetics was considered as a potent technology for sophisticated regulation of target genes, which might be a promising tool for regenerative medicine. In this study, we used an optogenetic control system to precisely regulate the expression of  Lhx8  to promote efficient bone regeneration.    Methods  Quantitative real-time PCR and western blotting were used to detect the expression of  Lhx8  and osteogenic marker genes. Alkaline phosphatase staining and alizarin red staining were used to detect alkaline phosphatase activity and calcium nodules. A customized optogenetic expression system was constructed to regulate  Lhx8 , of which the expression was activated in blue light but not in dark. We also used a critical calvarial defect model for the analysis of bone regeneration in vivo. Moreover, micro-computed tomography (micro-CT), three-dimensional reconstruction, quantitative bone measurement, and histological and immunohistochemistry analysis were performed to investigate the formation of new bone in vivo.    Results  During the osteogenic differentiation of BMSCs, the expression levels of  Lhx8  increased initially but then decreased thereafter.  Lhx8  promoted the early proliferation of BMSCs but inhibited subsequent osteogenic differentiation. The optogenetic activation of  Lhx8  in BMSCs in the early stages of differentiation by blue light stimulation led to a significant increase in cell proliferation, thus allowing a sufficient number of differentiating BMSCs to enter the later osteogenic differentiation stage. Analysis of the critical calvarial defect model revealed that the pulsed optogenetic activation of  Lhx8  in transplanted BMSCs over a 5-day period led to a significant increase in the generation of bone in vivo.    Conclusions   Lhx8  plays a critical role in balancing proliferation and osteogenic differentiation in BMSCs. The optogenetic activation of  Lhx8  expression at early stage of BMSCs differentiation led to better osteogenesis, which would be a promising strategy for precise bone regeneration.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13287-021-02412-8.

Temporal induction of Lhx8 by optogenetic control system for efficient bone regeneration