Improved osteogenesis and upregulated immunogenicity in human placenta-derived mesenchymal stem cells primed with osteogenic induction medium

Abstract

BackgroundMesenchymal stem cells (MSCs) are widely used in cell-based therapy owing to their multilineage potential and low immunogenicity. However, low differentiation efficiency and unpredictable immunogenicity of allogeneic MSCs in vivo limit their success in therapeutic treatment. Herein, we evaluated the differentiation potential and immunogenicity of human placenta-derived MSCs manipulated with osteogenic priming and dedifferentiation process.MethodsMSCs from human placentas were subjected to osteogenic induction and then cultivated in osteogenic factor-free media; the obtained cell population was termed dedifferentiated mesenchymal stem cells (De-MSCs). De-MSCs were induced into osteo-, chondro- and adipo-differentiation in vitro. Cell proliferation was quantified by a Cell-Counting Kit-8 or tritiated thymidine ([3H]-TdR) incorporation. Meanwhile, the osteogenesis of De-MSCs in vivo was assayed by real-time PCR and histological staining. The expressions of stem cell markers and co-stimulatory molecules on De-MSCs and lymphocytes from primed BALB/c mouse with De-MSCs were determined by flow cytometry.ResultsDe-MSCs exhibited some properties similar to MSCs including multiple differentiation potential and hypoimmunogenicity. Upon re-osteogenic induction, De-MSCs exhibited higher differentiation capability than MSCs both in vitro and in vivo. Of note, De-MSCs had upregulated immunogenicity in association with their osteogenesis, reflected by the alternated expressions of co-stimulatory molecules on the surface and decreased suppression on T cell activation. Functionally, De-MSC-derived osteoblasts could prime lymphocytes of peripheral blood and spleen in BALB/c mice in vivo.ConclusionsThese data are of great significance for the potential application of De-MSCs as an alternative resource for regenerative medicine and tissue engineering. In order to avoid being rejected by the host during allogeneic De-MSC therapy, we suggest that immune intervention should be considered to boost the immune acceptance and integration because of the upregulated immunogenicity of De-MSCs with redifferentiation in clinical applications.

Anti-Donor Immune Responses Elicited by Allogeneic Mesenchymal Stem Cells and Their Extracellular Vesicles: Are We Still Learning?

“…More important than cell surface expression levels is functional immunogenicity, which is the response of immune cells to the differentiated cells. Differentiated MSC have been shown to elicit allogeneic lymphocyte proliferation after osteogenic ( 34 ), chondrogenic ( 29 , 35 ), and hepatocytic ( 30 ) differentiation, and lymphocyte IFN-γ production in vitro after hepatocytic differentiation ( 30 ). Contrary to these studies, it has also been recently shown that differentiated MSC do not induce allogeneic T cell proliferation in vitro after osteogenic ( 36 ) or chondrogenic ( 37 ) differentiation.…”

“…For example, hepatocyte differentiated MSC induced significantly more CD3 + and CD45 + cells after transplantation compared to undifferentiated MSC, despite the fact that the differentiated MSC exerted a beneficial effect on the glycemic control of the treated animals ( 33 ). Osteogenically differentiated MSC transplantation resulted in significantly more activated immune cells after implantation in a mouse model ( 34 ). In a diabetic model, evidence for in situ differentiation was observed, increased numbers of cytotoxic cells in recipients and higher levels of allo-antibody were attributed to this differentiation ( 40 ).…”

Strontium Promotes the Proliferation and Osteogenic Differentiation of Human Placental Decidual Basalis- and Bone Marrow-Derived MSCs in a Dose-Dependent Manner

“…They can undergo osteogenic differentiation when cultured in the traditional osteogenic medium or stimulated by the osteogenic growth factors (e.g., bone morphogenic proteins) in vitro [11]. When grafted in combination with osteoinductive scaffolds, they are able to form bone tissue at the ectopic sites [12, 13]. Noticeably, they also enhanced bone regeneration after transplantation at the bone defects [14, 15].…”

A novel phosphorylation by AMP-activated kinase regulates RUNX2 from ubiquitination in osteogenesis over adipogenesis

“…Several studies reported that the reciprocal relationship between adipogenesis and osteogenesis from MSCs is determined by a combination of regulatory signaling pathways induced by bone marrow niche; however, there are some missing links that exit within this complex stimuli. It has been appropriately demonstrated that lineage-specific transcriptional regulators, RUNX2, DLX5 and Osterix, favor osteoblasts 8 , 9 , whereas the CEBP (CCAAT/enhancer binding protein) family (α, β, δ) and PPARγ2 (peroxisome proliferator-activated receptor-γ2) favor adipocytes 10 , 11 . However, the commitment of adipogenesis over osteogenesis or vice versa and the transdifferentiation process of the committed cell type, particularly under pathological conditions, is still not clear.…”