Background: Hematopoietic reconstitution following high-dose radiotherapy and chemotherapy is closely regulated by the hematopoietic microenvironment. Our previous study, using radiation-induced injury as a model, demonstrated that surviving bone marrow macrophages (BM-Mφ) respond to mechanical tension induced by marrow ablation through the Piezo1 channel. Depletion of BM-Mφ in mice hindered hematopoietic reconstitution and was accompanied by a reduction in the number of CD105+ bone marrow mesenchymal stem cells (BM-MSCs). This suggests that BM-Mφ, through Piezo1 activation, may regulate hematopoietic reconstitution by influencing the quantity and function of CD105+ BM-MSCs.

Methods: Bone marrow macrophages (BM-Mφ) were isolated from C57 mice, treated with the Piezo1 agonist (Yoda1), and the expression of TGF-β1 was detected by qPCR and Western blotting. BM-MSCs were isolated from C57 mice. CD105+ and CD105- subpopulations of primary BM-MSCs were sorted by magnetic beads. Recombinant TGF-β1 protein was used to treat BM-MSCs. The CCK8 assay was used to detect proliferation, flow cytometry was employed to analyze the cell cycle, alizarin red and oil red O staining were used to evaluate osteogenic and adipogenic differentiation, and qPCR and enzyme-linked immunosorbent assay were applied to detect the expression of CD105 and hematopoietic support factors (Lif, HGF, Ang II, IL-6, SCF, SDF).

Results: In BM-Mφ, compared with M0 and M1 types, Yoda1 (Piezo1 agonist) significantly upregulated the expression of TGF-β1 in M2-type BM-Mφ (P<0.05), and this effect was related to the anti-inflammatory and tissue repair functions of M2-type BM-Mφ. Compared with CD105-BM-MSCs, TGF-β1 significantly promoted the proliferation of CD105+ BM-MSCs (most obvious at 2ng/mL, P<0.05) and increased the proportion of cells in the S and G2 phases (P<0.05). 10ng/mL TGF-β1 enhanced osteogenic and adipogenic differentiation, and upregulated the expression of CD105 and hematopoietic factors such as SCF and HGF (P<0.05) in CD105+ BM-MSCs. Our resulters suggest that BM-Mφ responds to mechanical stimuli through Piezo1 providing an initial signal for TGF-β1 to regulate BMSCs numbers and functions via CD105 and promote the repair of the hematopoietic microenvironment.

Conclusion: This study confirms the core role of the “Piezo1-TGF-β1-CD105” pathway: mechanical signals activate BM-Mφ to secrete TGF-β1 via Piezo1, and the latter enhances the proliferation, differentiation, and hematopoietic support capabilities of BM-MSCs in a CD105-dependent manner, ultimately promoting the repair of the hematopoietic microenvironment. This pathway provides a new targeting strategy for hematopoietic reconstruction after radiation injury and has important clinical transformation value.

Keywords: Transforming growth factor-β1; CD105; Bone marrow mesenchymal stem cells; Hematopoietic microenvironment; Piezo1

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2025
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