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Osteoblast-derived mitochondria formulated with cationic liposome guide mesenchymal stem cells into osteogenic differentiation

ABSTRACT: While mitochondria are known to be essential for intracellular energy production and overall function, emerging evidence highlights their importance in influencing cell behavior intracellularly through mitochondrial transfer. This phenomenon provides a potential basis for the development of treatment strategies for tissue damage and degeneration and inhibition of tumor progression. This study aimed to evaluate whether mitochondria isolated from osteoblasts can promote osteogenic differentiation in mesenchymal stem cells (MSCs). We first compared mitochondria from MSCs, which primarily utilize glycolysis, with those from MG63 cells, which depend on OXPHOS. Mitochondria from both cell types were then encapsulated in cationic liposomes and transferred to MSCs and their impact on differentiation was assessed. Mitochondria delivery from MG63 cells to MSCs grown in both 2D and 3D cultures resulted in increased expression of osteogenic markers including RUNX2, OSX, and OPN and upregulation of genes involved in BMP2 signaling and calcium import. This was accompanied by increased calcium influx and regulated by the Wnt/b-catenin signaling pathway. Transplantation of spheroids containing MSCs with MG63-derived mitochondria in bone defect animal models improved bone regeneration. Our results suggest that delivery of MG63-derived mitochondria effectively guides MSCs toward osteogenesis, paving the way for the development of mitochondria-based therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279815 | GEO | 2025/04/02

REPOSITORIES: GEO

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Project description:We have previously reported that the deficiency of p53 alone or in combination with Rb (Rb-/- p53-/-) in adipose-derived MSCs (ASCs) promotes leiomyosarcoma-like tumors in vivo. Here, we hypothesized that the source of MSCs and/or the cell differentiation stage could determine the phenotype of sarcoma development. To investigate whether there is a link between the source of MSCs and sarcoma phenotype, we generated p53-/- and Rb-/-p53-/- MSCs from bone marrow (BM-MSCs). Both genotypes of BM-MSCs initiated leiomyosarcoma formation similar to p53-/- and Rb-/-p53-/- ASCs. In addition, gene expression profiling revealed a link between p53- or Rb-p53-deficient BM-MSCs and ASCs and muscle-associated sarcomagenesis. These data suggest that the tissue source of MSC does not seem a crucial factor in the development of a particular sarcoma phenotype. To analyze whether the differentiation stage defines the sarcoma phenotype, BM-MSCs and ASCs were induced to differentiate towards the osteogenic lineage, and both p53 and Rb were excised using Cre-expressing adenovectors at different stages along osteogenic differentiation. Regardless of the level of osteogenic commitment, the inactivation of Rb and p53 in BM-MSC-derived, but not in ASC-derived, osteogenic progenitors gave rise to osteosarcoma-like tumors which could be serially transplanted. This indicates that the osteogenic differentiation stage of BM-MSCs imposes the phenotype of in vivo sarcoma development, and that BM-MSC-derived osteogenic progenitors rather than undifferentiated BM-MSCs, undifferentiated ASCs or ASC-derived osteogenic progenitors, represent the cell of origin for osteosarcoma development. To analyse whether the BM-MSC and Fat-MSC (ASC) differentiation stage may define the sarcoma phenotype, RbloxP/loxPp53loxP/loxP BM-MSCs and ASCs were induced to differentiate towards the osteogenic lineage and both Rb and p53 were excised with adenoviral vectors expressing the Cre-recombinase gene (Ad-CMV-Cre) at different stages (day 0 and 10) along osteogenic differentiation. NSG mice were inoculated subcutaneously with 5M-CM-^W10^6 mutant cells. Animals were killed when tumors reached 1 cm3 or 150 days after infusion. Some of the obtained tumors were mechanically disaggregated to establish ex vivo MSC-transformed cell lines. Gene expression analysis was performed using: WT BM-MSCs and ASCs, Rb-/-p53-/- BM-MSCs and ASCs previously differentiated to the osteogenic lineage for 10 days and a tumor cell line derived from p53-/-Rb-/- BM-MSC differentiated to the osteogenic lineage for 10 days.

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Osteoblast-derived mitochondria formulated with cationic liposome guide mesenchymal stem cells into osteogenic differentiation

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