Strontium regulates stem cell fate during osteogenic differentiation through asymmetric cell division

Strontium, a popular osteogenic component, has been incorporated into various types of orthopaedic biomaterials to enhance bone regeneration. Strontium performs dual effects in promoting bone formation and inhibiting bone resorption. Previous studies have focused on the effects of strontium ions (Sr²⁺) in regulating stem cell behavior to initiate regenerative capacity. However, its mechanisms for regulating the fate and homeostasis of stem cells have not been fully elucidated. In this study, the promotive effect of Sr²⁺ on the osteogenic differentiation of mesenchymal stem cells was confirmed both in vitro and in vivo. Interestingly, in response to Sr²⁺ treatment, stem cells performed asymmetric cell division to balance stemness maintenance and osteogenic differentiation. In initiating osteogenic differentiation, Sr²⁺ maintained more cells in the cell cycle by upregulating the population of S and G2/M phase cells, and this increase in the cell population contributed to enhanced osteogenic differentiation. The divided cells with different cell fates were observed, with one daughter cell maintained stemness, while the other committed to osteogenic lineage. Further investigation revealed that Sr²⁺ activated noncanonical Wnt signaling to regulate the expression and distribution of the Par complex, thus regulating cell division. As a result, the daughter cells committed to different cell fates due to the discriminately activation of osteogenic transcription factors caused by asymmetrically distributed Par3 and aPKC. The results of this study could facilitate the design of biomaterials for bone regeneration by providing a better understanding of cell fate determination regulated by strontium.