KLF2+ stemness maintains human mesenchymal stem cells in bone regeneration

Abstract

Mesenchymal stem cells (MSCs), which are undifferentiated stem cells with the property of stemness and the potential to differentiate into multiple lineages, including osteoblasts, have attracted a great deal of attention in bone tissue engineering. Consistent with the heterogeneity of MSCs, various surface markers have been used. However, it is still unclear which markers of MSCs are best for cell amplification in vitro and later bone regeneration in vivo. Krüppel‐like Factor 2 (KLF2) is an important indicator of the stemness of human MSCs (hMSCs) and as early vascularization is also critical for bone regeneration, we used KLF2 as a novel in vitro marker for MSCs and investigated the angiogenesis and osteogenesis between KLF2+ MSCs and endothelial cells (ECs). We found a synergistic interaction between hMSCs and human umbilical vein ECs (HUVECs) in that KLF2+ stemness‐maintained hMSCs initially promoted the angiogenesis of HUVECs, which in turn more efficiently stimulated the osteogenesis of hMSCs. In fact, KLF2+ hMSCs secreted angiogenic factors initially, with some of the cells then differentiating into pericytes through the PDGF‐BB/PDGFR‐β signaling pathway, which improved blood vessel formation. The matured HUVECs in turn synergistically enhanced the osteogenesis of KLF2+ hMSCs through upregulated vascular endothelial growth factor. A three‐dimensional coculture model using cell‐laden gelatin methacrylate (GelMA) hydrogel further confirmed these results. This study provides insight into the stemness‐directed synergistic interaction between hMSCs and HUVECs, and our results will have a profound impact on further strategies involving the application of KLF2+ hMSC/HUVEC‐laden GelMA hydrogel in vascular network bioengineering and bone regeneration.

RETRACTED ARTICLE: MicroRNA-15b shuttled by bone marrow mesenchymal stem cell-derived extracellular vesicles binds to WWP1 and promotes osteogenic differentiation

“…Besides, our results were supported by a previous study whereby WWP1 promoted ubiquitination and degradation of KLF2 [14]. KLF2 has been revealed to play an important role in maintaining the stemness of hMSCs during bone regeneration [24]. Similarly, the silencing of KLF2 has been reported to repress osteoblast differentiation [25].…”

CDR1as regulated by hnRNPM maintains stemness of periodontal ligament stem cells via miR‐7/KLF4

“…A critical requirement in periodontal tissue regeneration is the stemness of a PDLSC-enriched population that retains the features of its original constituent cells. 24 Stemness of PDLSCs is closely related to age, oestrogen levels, hypoxia and the inflammatory microenvironment, strongly limiting their usefulness in tissue engineering. [25][26][27][28] Maintaining stemness of PDLSCs might provide a new strategy for repair of injured periodontal tissue and in situ regeneration.…”

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“…Although previous research efforts have provided evidence for the existence of MSC subpopulations with distinct differentiation propensities, we currently lack the ability to identify and isolate MSCs with high‐self renewal capacity and elevated osteogenic potential. A previous study from the laboratories of Mengfei Yu and Huiming Wang (Zhejiang University, Hangzhou, China) identified the KLF2 transcription factor as an important contributor to the proliferation and pluripotency of MSCs derived from human bone‐marrow, and in their recent STEM CELLS article, the authors report their findings regarding the osteogenic potential of KLF2‐expressing hMSCs . Briefly, Zhou et al investigated a combination of KLF2‐expressing hMSCs and human umbilical vein endothelial cells, given the requirement for an adequate blood supply for optimized tissue regeneration outcomes .…”

“…Current hurdles to their widespread implementation include the lack of markers for the isolation of specific MSC subpopulations with elevated osteogenic potential and also the provision of those in vivo conditions, such as the adequate supply of growth factors and an optimized growth matrix, conducive for MSC survival, high levels of osteogenic differentiation, and the repair of critically‐sized defects. In our second Featured Article published this month in STEM CELLS , Zhou et al describe a synergistic interaction between Krüppel‐like factor 2 (KLF2)‐expressing human (h)MSCs and endothelial cells that may significantly influence future bone regeneration and vascular network bioengineering strategies . In a Related Article recently published in STEM CELLS Translational Medicine , Andrews et al compared bone repair techniques and demonstrated the utility of a bone morphogenetic protein 2 (BMP‐2)‐releasing chondroitin sulfate glycosaminoglycan scaffold as a means to support large bone defect healing by engineered MSCs …”