PMID- 35995408 OWN - NLM STAT- MEDLINE DCOM- 20220929 LR - 20221116 IS - 1878-7568 (Electronic) IS - 1742-7061 (Linking) VI - 151 DP - 2022 Oct 1 TI - Microfluidic evidence of synergistic effects between mesenchymal stromal cell-derived biochemical factors and biomechanical forces to control endothelial cell function. PG - 346-359 LID - S1742-7061(22)00500-1 [pii] LID - 10.1016/j.actbio.2022.08.025 [doi] AB - A functional vascular system is a prerequisite for bone repair as disturbed angiogenesis often causes non-union. Paracrine factors released from human bone marrow derived mesenchymal stromal cells (BMSCs) have angiogenic effects on endothelial cells. However, whether these paracrine factors participate in blood flow dynamics within bone capillaries remains poorly understood. Here, we used two different microfluidic designs to investigate critical steps during angiogenesis and found pronounced effects of endothelial cell proliferation as well as chemotactic and mechanotactic migration induced by BMSC conditioned medium (CM). The application of BMSC-CM in dynamic cultures demonstrates that bioactive factors in combination with fluidic flow-induced biomechanical signals significantly enhanced endothelial cell migration. Transcriptional analyses of endothelial cells demonstrate the induction of a unique gene expression profile related to tricarboxylic acid cycle and energy metabolism by the combination of BMSC-CM factors and shear stress, which opens an interesting avenue to explore during fracture healing. Our results stress the importance of in vivo - like microenvironments simultaneously including biochemical, biomechanical and oxygen levels when investigating key events during vessel repair. STATEMENT OF SIGNIFICANCE: Our results demonstrate the importance of recapitulating in vivo - like microenvironments when investigating key events during vessel repair. Endothelial cells exhibit enhanced angiogenesis characteristics when simultaneous exposing them to hMSC-CM, mechanical forces and biochemical signals simultaneously. The improved angiogenesis may not only result from the direct effect of growth factors, but also by reprogramming of endothelial cell metabolism. Moreover, with this model we demonstrated a synergistic impact of mechanical forces and biochemical factors on endothelial cell behavior and the expression of genes involved in the TCA cycle and energy metabolism, which opens an interesting new avenue to stimulate angiogenesis during fracture healing. CI - Copyright (c) 2022. Published by Elsevier Ltd. FAU - Zhang, Shuang AU - Zhang S AD - Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus University Medical Center; Rotterdam, the Netherlands. FAU - Tuk, Bastiaan AU - Tuk B AD - Department of Plastic and Reconstructive Surgery, Erasmus University Medical Center; Rotterdam, the Netherlands. FAU - van de Peppel, Jeroen AU - van de Peppel J AD - Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus University Medical Center; Rotterdam, the Netherlands. FAU - Kremers, Gert-Jan AU - Kremers GJ AD - Erasmus Optical Imaging Center, Erasmus University Medical Center; Rotterdam, the Netherlands. FAU - Koedam, Marijke AU - Koedam M AD - Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus University Medical Center; Rotterdam, the Netherlands. FAU - Pesch, Georg R AU - Pesch GR AD - Department of Chemical Engineering, Delft University of Technology; Delft, the Netherlands. FAU - Rahman, Zaid AU - Rahman Z AD - Department of Chemical Engineering, Delft University of Technology; Delft, the Netherlands. FAU - Hoogenboezem, Remco M AU - Hoogenboezem RM AD - Department of Hematology, Erasmus University Medical Center; Rotterdam, the Netherlands. FAU - Bindels, Eric M J AU - Bindels EMJ AD - Department of Hematology, Erasmus University Medical Center; Rotterdam, the Netherlands. FAU - van Neck, Johan W AU - van Neck JW AD - Department of Plastic and Reconstructive Surgery, Erasmus University Medical Center; Rotterdam, the Netherlands. FAU - Boukany, Pouyan E AU - Boukany PE AD - Department of Chemical Engineering, Delft University of Technology; Delft, the Netherlands. FAU - van Leeuwen, Johannes P T M AU - van Leeuwen JPTM AD - Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus University Medical Center; Rotterdam, the Netherlands. FAU - van der Eerden, Bram C J AU - van der Eerden BCJ AD - Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus University Medical Center; Rotterdam, the Netherlands. Electronic address: b.vandereerden@erasmusmc.nl. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220820 PL - England TA - Acta Biomater JT - Acta biomaterialia JID - 101233144 RN - 0 (Culture Media, Conditioned) RN - S88TT14065 (Oxygen) SB - IM MH - Culture Media, Conditioned/metabolism/pharmacology MH - *Endothelial Cells MH - Humans MH - *Mesenchymal Stem Cells MH - Microfluidics MH - Neovascularization, Physiologic MH - Oxygen/pharmacology OTO - NOTNLM OT - Angiogenesis OT - Endothelial cell OT - Mesenchymal stromal cell OT - Microfluidics COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/08/23 06:00 MHDA- 2022/09/30 06:00 CRDT- 2022/08/22 19:37 PHST- 2022/03/28 00:00 [received] PHST- 2022/07/20 00:00 [revised] PHST- 2022/08/12 00:00 [accepted] PHST- 2022/08/23 06:00 [pubmed] PHST- 2022/09/30 06:00 [medline] PHST- 2022/08/22 19:37 [entrez] AID - S1742-7061(22)00500-1 [pii] AID - 10.1016/j.actbio.2022.08.025 [doi] PST - ppublish SO - Acta Biomater. 2022 Oct 1;151:346-359. doi: 10.1016/j.actbio.2022.08.025. Epub 2022 Aug 20.