Abstract Mesenchymal stem cells (MSC) hold promise in promoting vascular regeneration of ischemic tissue in conditions like critical limb ischemia of the leg. However, this approach has been limited in part by poor cell retention and survival after delivery. New biomaterials offer an opportunity to localize cells to the desired tissue after delivery, but also to improve cell survival after delivery. Here we characterize the mechanical and microstructural properties of a novel hydrogel composed of pooled human platelet lysate (PL) and test its ability to promote MSC angiogenic activity using clinically relevant in vitro and in vivo models. This PL hydrogel had comparable storage and loss modulus and behaved as a viscoelastic solid similar to fibrin hydrogels despite having 1/4–1/10th the fibrin content of standard fibrin gels. Additionally, PL hydrogels enabled sustained release of endogenous PDGF-BB for up to 20 days and were resistant to protease degradation. PL hydrogel stimulated pro-angiogenic activity by promoting human MSC growth and invasion in a 3D environment, and enhancing endothelial cell sprouting alone and in co-culture with MSCs. When delivered in vivo , the combination of PL and human MSCs improved local tissue perfusion after 8 days compared to controls when assessed with laser Doppler perfusion imaging in a murine model of hind limb ischemia. These results support the use of a PL hydrogel as a scaffold for MSC delivery to promote vascular regeneration. Statement of Significance Innovative strategies for improved retention and viability of mesenchymal stem cells (MSCs) are needed for cellular therapies. Human platelet lysate is a potent serum supplement that improves the expansion of MSCs. Here we characterize our novel PL hydrogel’s desirable structural and biologic properties for human MSCs and endothelial cells. PL hydrogel can localize cells for retention in the desired tissue, improves cell viability, and augments MSCs’ angiogenic activity. As a result of these unique traits, PL hydrogel is ideally suited to serve as a cell delivery vehicle for MSCs injected into ischemic tissues to promote vascular regeneration, as demonstrated here in a murine model of hindlimb ischemia.
Last. Todd C. McDevitt(Georgia Institute of Technology)H-Index: 37
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Background Critical limb ischemia (CLI) is a life- and limb-threatening condition affecting 1% to 10% of the population with peripheral arterial disease. Traditional revascularization options are not possible for up to 50% of CLI patients, in which case, the use of cellular therapies, such as bone marrow-derived mesenchymal stem cells (MSCs), hold great promise as an alternative revascularization therapy. However, no randomized, controlled phase 3 trials to date have demonstrated an improvement ...
Last. W. Robert Taylor(Georgia Institute of Technology)H-Index: 49
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Stem cell-based therapies hold great promise as a clinically viable approach for vascular regeneration. Preclinical studies have been very encouraging and early clinical trials have suggested favourable outcomes. However, significant challenges remain in terms of optimizing cell retention and maintenance of the paracrine effects of implanted cells. To address these issues, we have proposed the use of a cellular encapsulation approach to enhance vascular regeneration. We contained human mesenchym...
Critical limb ischemia (CLI) is often poorly treatable by conventional management and alternatives such as autologous cell therapy are increasingly investigated. Whereas previous studies showed a substantial impairment of neovascularization capacity in primary bone-marrow (BM) isolates from patients, little is known about dysfunction in patient-derived BM mesenchymal stromal cells (MSCs). In this study, we have compared CLI-MSCs to healthy controls using gene expression profiling and functional ...
Last. Yanan Du(THU: Tsinghua University)H-Index: 30
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f Harvard-Massachusetts The promise of cell therapy for repair and restoration of damaged tissues or organs relies on administration of large dose of cells whose healing benefits are still limited and sometimes irreproduc- ible due to uncontrollable cell loss and death at lesion sites. Using a large amount of therapeutic cells increases the costs for cell processing and the risks of side effects. Optimal cell delivery strate- gies are therefore in urgent needto enhance the specificity, efficacy,...
Last. Elena P. Ivanova(Swinburne University of Technology)H-Index: 51
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Two non-pigmented, motile, Gram-negative marine bacteria designated R9SW1 T and A3d10 T were isolated from sea water samples collected from Chazhma Bay, Gulf of Peter the Great, Sea of Japan, Pacific Ocean, Russia and St. Kilda Beach, Port Phillip Bay, the Tasman Sea, Pacific Ocean, respectively. Both organisms were found to grow between 4uC and 40uC, between pH 6 to 9, and are moderately halophilic, tolerating up to 20% (w/v) NaCl. Both strains were found to be able to degrade Tween 40 and 80, ...
Endothelial colony-forming cells (ECFCs) are endothelial precursors that circulate in peripheral blood. Studies have demonstrated that human ECFCs have robust vasculogenic properties. However, whether ECFCs can exert trophic functions in support of specific stem cells in vivo remains largely unknown. Here, we sought to determine whether human ECFCs can function as paracrine mediators before the establishment of blood perfusion. We used two xenograft models of human mesenchymal stem cell (MSC) tr...
Last. Roberto Bolli(University of Louisville)H-Index: 104
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Although transplantation of c-kit+ cardiac stem cells (CSCs) has been shown to alleviate left ventricular (LV) dysfunction induced by myocardial infarction (MI), the number of exogenous CSCs remaining in the recipient heart following transplantation and their mechanism of action remain unclear. We have previously developed a highly sensitive and accurate method to quantify the absolute number of male murine CSCs in female recipient organs after transplantation. In the present study, we used this...
Last. Luca Pierelli(Sapienza University of Rome)H-Index: 34
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Background Supplements to support clinical-grade cultures of mesenchymal stem cells (MSC) are required to promote growth and expansion of these cells. Platelet lysate (PL) is a human blood component which may replace animal serum in MSC cultures being rich in various growth factors. Here, we describe a plasma poor pathogen-free platelet lysate obtained by pooling 12 platelet (PLT) units, to produce a standardized and safe supplement for clinical-grade expansion of MSC.
Platelet-rich plasma (PRP) as a clinical treatment for bone, muscle, tendon, and cartilage injury has gained popularity in the field of orthopedic sports medicine. The use of a patient’s own blood is an appealing aspect of PRP treatment, as the resulting plasma preparation is considered relatively b
#1Sarah Griffiths(Parker H. Petit Institute for Bioengineering & Bioscience)H-Index: 8
#2Priya R. Baraniak(The Wallace H. Coulter Department of Biomedical Engineering)H-Index: 4
Last. Todd C. McDevitt(Parker H. Petit Institute for Bioengineering & Bioscience)H-Index: 37
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Abstract Background aims Multipotent mesenchymal stromal cells (MSCs) are clinically useful because of their immunomodulatory and regenerative properties, but MSC therapies are limited by the loss of self-renewal and cell plasticity associated with ex vivo expansion culture and, on transplantation, increased immunogenicity from xenogen exposure during culture. Recently, pooled human platelet lysate (hPL) has been used as a culture supplement to promote MSC growth; however, the effects of hPL on ...
Critical limb ischemia (CLI) is the most severe clinical manifestation of peripheral arterial disease (PAD), resulting in the total or partial loss of limb function. Although the conventional treatment strategy of CLI (e.g., medical treatment and surgery) can improve blood perfusion and restore limb function, many patients are unsuitable for these strategies and they still face the threats of amputation or death. Therapeutic angiogenesis, as a potential solution for these problems, attempts to m...
Abstract Wounds impact millions of patients every year and represent a serious cause of morbidity and mortality worldwide, yet current treatment outcomes are far from ideal. Therapies based on delivery of multiple growth factors offer a promising approach for optimal wound management; however, their high production cost, low stability, and lack of effective delivery system limits their application in the clinic. Platelet lysate is a suitable, abundant and cost-effective source of growth factors ...
#2Andrew C. Daly(UPenn: University of Pennsylvania)H-Index: 12
Last. Jason A. Burdick(UPenn: University of Pennsylvania)H-Index: 90
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Abstract Towards the repair of damaged tissues, numerous scaffolds have been fabricated to recreate the complex extracellular matrix (ECM) environment to support desired cell behaviors; however, it is often challenging to design scaffolds with the requisite cell-anchorage sites, mechanical stability, and tailorable physicochemical properties necessary for many applications. To address this and to improve on the properties of hyaluronic acid (HA) hydrogels, we combined photocrosslinkable norborne...