Platelet-Therapeutics to Improve Tissue Regeneration and Wound Healing—Physiological Background and Methods of Preparation

Jansen, Ellen E; Braun, Andreas; Jansen, Patrick A.; Hartmann, Matthias

doi:10.3390/biomedicines9080869

Cited by 18 publications

(13 citation statements)

References 90 publications

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“…Platelets are key players in primary hemostasis preventing blood loss at sites of vascular injury [ 1 ], but also in innate and adaptive immune defense [ 2 ]. They support wound healing by secreting growth factors, such as platelet-derived growth factor β (PDGF-β), or by stimulating resident stromal cells to secrete cytokines inducing wound healing and tissue regeneration [ 3 , 4 , 5 ]. Despite initial enthusiasm, the broad application of platelet-derived products in regenerative medicine is hampered by a lack of definitive evidence [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Synergy of Human Platelet-Derived Extracellular Vesicles with Secretome Proteins Promotes Regenerative Functions

et al. 2022

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Platelet-rich plasma is a promising regenerative therapeutic with controversial efficacy. We and others have previously demonstrated regenerative functions of human platelet lysate (HPL) as an alternative platelet-derived product. Here we separated extracellular vesicles (EVs) from soluble factors of HPL to understand the mode of action during skin-organoid formation and immune modulation as model systems for tissue regeneration. HPL-EVs were isolated by tangential-flow filtration (TFF) and further purified by size-exclusion chromatography (SEC) separating EVs from (lipo)protein-enriched soluble fractions. We characterized samples by tunable resistive pulse sensing, western blot, tandem mass-tag proteomics and super-resolution microscopy. We evaluated EV function during angiogenesis, wound healing, organoid formation and immune modulation. We characterized EV enrichment by TFF and SEC according to MISEV2018 guidelines. Proteomics showed three major clusters of protein composition separating TSEC-EVs from HPL clustering with TFF soluble fractions and TFF-EVs clustering with TSEC soluble fractions, respectively. HPL-derived TFF-EVs promoted skin-organoid formation and inhibited T-cell proliferation more efficiently than TSEC-EVs or TSEC-soluble fractions. Recombining TSEC-EVs with TSEC soluble fractions re-capitulated TFF-EV effects. Zeta potential and super-resolution imaging further evidenced protein corona formation on TFF-EVs. Corona depletion on SEC-EVs could be artificially reconstituted by TSEC late fraction add-back. In contrast to synthetic nanoparticles, which commonly experience reduced function after corona formation, the corona-bearing EVs displayed improved functionality. We conclude that permissive isolation technology, such as TFF, and better understanding of the mechanism of EV corona function are required to realize the complete potential of platelet-based regenerative therapies.

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Section: Introductionmentioning

confidence: 99%

Synergy of Human Platelet-Derived Extracellular Vesicles with Secretome Proteins Promotes Regenerative Functions

et al. 2022

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“…Inside-out signaling is achieved by the activation of G protein-coupled receptors via the agonists thrombin, thromboxane A2, ADP, epinephrine, and collagen and subsequent phospholipase C, β, or γ (dependent on the agonist) activation. Phospholipase C, in turn, hydrolyzes phosphatidylinositol (4,5)-bisphosphate into diacylglycerol and inositol (1,4,5) triphosphate. As a consequence, the guanine nucleotide exchange factor activates the GTPase RAS-related protein 1.…”

Section: Signal Transduction Of αIibβ3mentioning

confidence: 99%

“…Coagulation is characterized by the formation of a fibrin mesh which includes platelets as well as red blood cells and leucocytes. The aim of clot formation is the achievement of hemostasis and tissue repair [1]. Platelets have an active role in this process, releasing hundreds of mediators and influencing clot strength and volume.…”

Section: Introductionmentioning

confidence: 99%

Clot Retraction: Cellular Mechanisms and Inhibitors, Measuring Methods, and Clinical Implications

Jansen

Hartmann

2021

Biomedicines

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Platelets have important functions in hemostasis. Best investigated is the aggregation of platelets for primary hemostasis and their role as the surface for coagulation leading to fibrin- and clot-formation. Importantly, the function of platelets does not end with clot formation. Instead, platelets are responsible for clot retraction through the concerted action of the activated αIIbβ3 receptors on the surface of filopodia and the platelet’s contractile apparatus binding and pulling at the fibrin strands. Meanwhile, the signal transduction events leading to clot retraction have been investigated thoroughly, and several targets to inhibit clot retraction have been demonstrated. Clot retraction is a physiologically important mechanism allowing: (1) the close contact of platelets in primary hemostasis, easing platelet aggregation and intercellular communication, (2) the reduction of wound size, (3) the compaction of red blood cells to a polyhedrocyte infection-barrier, and (4) reperfusion in case of thrombosis. Several methods have been developed to measure clot retraction that have been based on either the measurement of clot volume or platelet forces. Concerning the importance of clot retraction in inborn diseases, the failure of clot retraction in Glanzmann thrombasthenia is characterized by a bleeding phenotype. Concerning acquired diseases, altered clot retraction has been demonstrated in patients with coronary heart disease, stroke, bronchial asthma, uremia, lupus erythematodes, and other diseases. However, more studies on the diagnostic and prognostic value of clot retraction with methods that have to be standardized are necessary.

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“…Whether antiplatelet drugs can be used to reduce low-grade inflammation, a possible driver of cardiovascular disease [60], remains to be determined and it is challenging to pinpoint such effects on platelets. In addition, given the beneficial effects of platelets and their released contents in wound healing processes [61], inhibition of chemokine release might not always be advantageous.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Combined Antiplatelet Therapy Reduces the Proinflammatory Properties of Activated Platelets

Heinzmann

Coenen

Vajen

et al. 2021

TH Open

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The cause of atherothrombosis is rupture or erosion of atherosclerotic lesions, leading to an increased risk on myocardial infarction or stroke. Here, platelet activation plays a major role, leading to the release of bioactive molecules, e.g. chemokines and coagulation factors, and to platelet clot formation. Several antiplatelet therapies have been developed for secondary prevention of cardiovascular events, in which anticoagulant drugs are often combined. Besides playing a role in haemostasis, platelets are also involved in inflammation. However, it is unclear whether current antiplatelet therapies also affect platelet immune functions. In this study, the possible anti-inflammatory effects of antiplatelet medications on chemokine release were investigated using ELISA and on the chemotaxis of THP-1 cells towards platelet releasates. The cause of atherothrombosis is rupture or erosion of atherosclerotic lesions, leading to an increased risk on myocardial infarction or stroke. Here, platelet activation plays a major role, leading to the release of bioactive molecules, e.g. chemokines and coagulation factors, and to platelet clot formation. Several antiplatelet therapies have been developed for secondary prevention of cardiovascular events, in which anticoagulant drugs are often combined. Besides playing a role in haemostasis, platelets are also involved in inflammation. However, it is unclear whether current antiplatelet therapies also affect platelet immune functions. In this study, the possible anti-inflammatory effects of antiplatelet medications on chemokine release were investigated using ELISA and on the chemotaxis of THP-1 cells towards platelet releasates. We found that antiplatelet medication acetylsalicylic acid (ASA) led to reduced chemokine (C-C motif) ligand 5 (CCL5) and chemokine (C-X-C motif) ligand 4 (CXCL4) release from platelets, while leukocyte chemotaxis was not affected. Depending on the agonist, αIIbβ3- and P2Y12-inhibitors also affected CCL5 or CXCL4 release. The combination of ASA with a P2Y12 inhibitor or a phosphodiesterase inhibitor did not lead to an additive reduction on CCL5 or CXCL4 release. Interestingly, these combinations did reduce leukocyte chemotaxis. This study provides evidence that combined therapy of ASA and a P2Y12 or PDE3 inhibitor can decrease the inflammatory leukocyte recruiting potential of the releasate of activated platelets.

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Platelet-Therapeutics to Improve Tissue Regeneration and Wound Healing—Physiological Background and Methods of Preparation

Cited by 18 publications

References 90 publications

Synergy of Human Platelet-Derived Extracellular Vesicles with Secretome Proteins Promotes Regenerative Functions

Synergy of Human Platelet-Derived Extracellular Vesicles with Secretome Proteins Promotes Regenerative Functions

Clot Retraction: Cellular Mechanisms and Inhibitors, Measuring Methods, and Clinical Implications

Combined Antiplatelet Therapy Reduces the Proinflammatory Properties of Activated Platelets

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