Pages 269-315) Effects DOI: of 10.22203/Ecm.V041a19platelet Products on Bio-Physiology ISSN of BM-Mscs1473-2262
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EuropeanJ Vun et al. Cells and Materials Vol. 41 2021 (pages 269-315) Effects DOI: of 10.22203/eCM.v041a19platelet products on bio-physiology ISSN of BM-MSCs1473-2262 THE IN VITRO EFFECTS OF PLATELET PRODUCTS ON THE BIOPHYSIOLOGICAL FUNCTIONS OF HUMAN BONE MARROW MESENCHYMAL STROMAL CELLS: A SYSTEMATIC REVIEW J. Vun1,2,3,*, M. Panteli1,2,3, E. Jones2 and P.V. Giannoudis1,2,3,4 1 Academic Department of Trauma and Orthopaedics, School of Medicine, University of Leeds, Leeds, UK 2 Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK 3 Leeds Orthopaedic and Trauma Sciences, Leeds General Infirmary, University of Leeds, Leeds, UK 4 NIHR Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds, UK Abstract Platelet products (PP) and bone-marrow aspirate are popular sources of osteoinductive signalling molecules and osteogenic bone marrow mesenchymal stromal cells (BM-MSCs) used in the treatment of impaired bone healing. However, the combined use of PP and BM-MSCs in clinical studies has reported mixed results. Understanding the cellular and molecular interactions between PP and BM-MSCs plays the important role of guiding future research and clinical application. This systematic review investigates the effects of PP on the biophysiological functions of BM-MSCs in in vitro human studies, including (i) proliferation, (ii) migration, (iii) differentiation, (iv) growth factor/cytokine/protein expression, (v) immunomodulation, (vi) chemotactic effect on haematopoietic stem cells, (vii) response to apoptotic stress, and (viii) gene expression.In vitro studies in human have demonstrated the multi-faceted ‘priming effect’ of PP on the biophysiological functions of BM-MSCs. PP has been shown to improve proliferation, migration, osteogenic differentiation, reaction to apoptotic stress as well as immunomodulatory, pro-angiogenic and pro-inflammatory capacities of BM- MSCs. Several factors are highlighted that restrict the transferability of these findings into clinical practice. Therefore, more collaborative in vitro research in humans modelled to reflect clinical practice is required to better understand the effects of PP exposure on the biophysiological function(s) of BM-MSCs in human. Keywords: Bone marrow mesenchymal stem cell(s), mesenchymal stromal cell(s), platelet-rich plasma, platelet lysate, platelet concentrate, platelet releasate, platelet gel, platelet-rich fibrin, bone healing, non-union. *Address for correspondence: Dr James Shen Hwa Vun, Clinical Research Fellow, Academic Department of Trauma and Orthopaedics, School of Medicine, University of Leeds, Clarendon Wing, Level A, Great George Street, Leeds, LS1 3EX, West Yorkshire, UK. Telephone number: +44 1133922750 Fax number: +44 113392329 Email: [email protected] Copyright policy: This article is distributed in accordance with Creative Commons Attribution Licence (http://creativecommons.org/licenses/by-sa/4.0/). List of Abbreviations BMP bone morphogenetic protein CEPBA CCAAT/enhancer-binding protein α αMEM alpha-minimum essential medium CFU colony-forming unit aPRP activated PRP CM conditioned medium ACAN aggrecan COL1 collagen type 1 ACD-A acid-citrate dextrose solution A COL1A1 collagen type 1 α1 ADIPOQ adiponectin, C1Q and collagen COL2A1 collagen type 2 α1 domain containing COMP cartilage oligomeric matrix protein aFGF acidic fibroblast growth factor COX-2 cyclooxygenase-2 ALP alkaline phosphatase CPD citrate phosphate dextrose APOE apolipoprotein E DAPI 4′,6-diamidino-2-phenylindole bFGF basic fibroblast growth factor DMEM Dulbecco′s modified Eagle′s medium BMA bone marrow aspirate EDTA ethylenediamine tetraacetic acid BMAC BMA concentrate FABP4 fatty acid binding protein 4 BM-MSCs bone marrow mesenchymal stromal FBS foetal bovine serum cells fPL filtered PL 269 www.ecmjournal.org J Vun et al. Effects of platelet products on bio-physiology of BM-MSCs FTPL frozen-thawed PL RUNX2 runt-related transcription factor 2 G-CSF granulocyte colony-stimulating SDF-1 stroma-derived factor-1 factor SEM scanning electron microscopy GLUT4 glucose transporter type 4 SNPL PL obtained by sonification HG-DMEM high-glucose DMEM SOX SRY-box transcription factor HGF hepatocyte growth factor SPARC secreted protein acidic and cysteine HPLF human platelet lysate from fresh rich platelet concentrates SREBP1 sterol regulatory element-binding HPLO human platelet lysate from expired transcription factor 1 platelet concentrates TERT telomerase reverse transcriptase HSCs haematopoietic stem cells TGF transforming growth factor IL interleukin ucPRP umbilical cord PRP IP-10 interferon-γ-inducible protein 10 uPA urokinase-type plasminogen iNOS inducible nitric oxide synthase activator ITS insulin-transferrin-selenium VEGF vascular endothelial growth factor KO-DMEM knock out-DMEM receptor L-PRP leukocyte-rich PRP L-PDGS lipocalin-type prostaglandin D synthase LG-DMEM low-glucose DMEM Introduction LPL lipoprotein lipase LXRα liver X receptor alpha Bone healing is a unique biological process leading MCP-1 monocyte chemoattractant protein-1 to bone repair and restoration of bone function to MMP matrix metalloproteinases its pre-injury level (Einhorn and Gerstenfeld, 2015). MNC mononuclear cell According to the ‘diamond concept’, bone healing MIP macrophage inflammatory protein involves the orchestrated interaction between naPPP non-activated PPP multiple factors at the molecular, physiological and naPRP non-activated PRP biomechanical level (Giannoudis et al., 2007). NF-κB nuclear factor kappa-light-chain- The three fundamental molecular components enhancer of activated B cells of bone healing are: (a) osteogenic progenitor cells, NM nutrient medium such as BM-MSCs; (b) osteoinductive signalling NO nitric oxide molecules, such as growth factors and cytokines; OM osteogenic differentiation medium (c) osteoconductive scaffold/matrix (Calori and PAI-1 plasminogen activator inhibitor-1 Giannoudis, 2011). In addition, other essential PBMC peripheral mononuclear cells factors at the physiological and biomechanical levels PD population doubling crucial to successful bone healing include the host PDGF platelet-derived growth factor (i.e. patient) physiology, mechanical stability and PG platelet gel vascularity of the affected local bone environment PG-CM platelet gel conditioned-medium (Giannoudis et al., 2008). PGE2 prostaglandin E2 Although every attempt has been made to PL platelet lysate optimise the physiological and biomechanical factors PLGF placental growth factor during primary surgery, impaired bone healing (e.g. PLIN perlipin delayed union and non-union) remains common, POU5F1 POU class 5 homeobox 1 occurring in 5-10 % of all acute fractures (Ekegren et PP platelet product al., 2018; Mills and Simpson, 2013). Impaired bone PPARG peroxisome proliferator-activated healing is challenging to treat and poses a significant receptor gamma burden on the patient, socioeconomic and healthcare PPP platelet-poor plasma systems (Bishop et al., 2012; Hak et al., 2014). Multiple P-PRP leukocyte-poor PRP operations are often required to achieve treatment PRISMA Preferred Reporting Items for success, which exposes patient to further risks of Systematic Reviews and Meta- peri-operative complications, prolonged periods of Analyses rehabilitation and delay in returning to work. From PR platelet releasate a socioeconomic perspective, the direct treatment PRC platelet-rich concentrate costs have been estimated to be between £7,000 and PRGF plasma rich in growth factors £79,000 per person depending on complexity (Bishop PRF platelet-rich fibrin et al., 2012). In European healthcare systems the PRP platelet-rich plasma indirect costs through productivity losses have been PRP-CM PRP-conditioned culture medium estimated to be 10 times higher (Hak et al., 2014). PTGES prostaglandin E synthase In an effort to optimise bone healing, surgeons RANTES regulated on activation, normal T have recently attempted a ‘polytherapy’ approach cell expressed and secreted involving the simultaneous application of all the www.ecmjournal.org 270 J Vun et al. Effects of platelet products on bio-physiology of BM-MSCs three fundamental molecular components of bone terminology that allows for the effective, accurate healing, as mentioned previously (Calori et al., 2011). description of these PPs, reflective of its contents and Autologous sources of these biological components, physical properties (e.g. liquid, gel, fibrin membrane). which guarantees histocompatibility, minimal Clinical studies investigating the use of PPs morbidity and ease of access during the harvesting either alone or in combination with BM-MSCs have process, are ultimately desirable. This has made reported mixed results (Andia and Maffulli, 2019; autologous iliac crest bone graft, PPs and BMA/ Bielecki et al., 2008; Calori et al., 2008; Chiang et al., BMAC popular sources of osteoconductive scaffolds, 2007; Etulain, 2018; Galasso et al., 2008; Golos et al., osteoinductive molecules and osteogenic BM-MSCs, 2014; Malhotra et al., 2015; Mariconda et al., 2008; respectively (Calori and Giannoudis, 2011; Gianakos Roffi et al., 2017; Sanchez et al., 2009; Say et al., 2014; et al., 2017; Roffi et al., 2017). Verboket et al., 2018). The pooling of fractures from PPs or platelet derivatives are terminologies often different anatomical sites (e.g. tibia, femur, humerus) used interchangeably to represent haemoderivatives (Bielecki et al., 2008; Calori et al., 2008; Chiang et al., containing platelets and growth factors, cytokines 2007; Galasso et