Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomaterials

Department of Surgery, Stanford University, GK 201, Stanford, CA 94305, USA.
Biomaterials (Impact Factor: 8.56). 09/2011; 33(1):80-90. DOI: 10.1016/j.biomaterials.2011.09.041
Source: PubMed


In this study, we examined the capacity of a biomimetic pullulan-collagen hydrogel to create a functional biomaterial-based stem cell niche for the delivery of mesenchymal stem cells (MSCs) into wounds. Murine bone marrow-derived MSCs were seeded into hydrogels and compared to MSCs grown in standard culture conditions. Hydrogels induced MSC secretion of angiogenic cytokines and expression of transcription factors associated with maintenance of pluripotency and self-renewal (Oct4, Sox2, Klf4) when compared to MSCs grown in standard conditions. An excisonal wound healing model was used to compare the ability of MSC-hydrogel constructs versus MSC injection alone to accelerate wound healing. Injection of MSCs did not significantly improve time to wound closure. In contrast, wounds treated with MSC-seeded hydrogels showed significantly accelerated healing and a return of skin appendages. Bioluminescence imaging and FACS analysis of luciferase+/GFP+ MSCs indicated that stem cells delivered within the hydrogel remained viable longer and demonstrated enhanced engraftment efficiency than those delivered via injection. Engrafted MSCs were found to differentiate into fibroblasts, pericytes and endothelial cells but did not contribute to the epidermis. Wounds treated with MSC-seeded hydrogels demonstrated significantly enhanced angiogenesis, which was associated with increased levels of VEGF and other angiogenic cytokines within the wounds. Our data suggest that biomimetic hydrogels provide a functional niche capable of augmenting MSC regenerative potential and enhancing wound healing.

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    • "While the delivery system, dose, and model varies widely across the many studies exploiting GHK and its analogues, the peptide is generally delivered using a controlled release system or by repeated administration (Pickart, 2008). Interestingly, when coupled to alginate hydrogels, GHK increased VEGF and FGF production by mesenchymal stem cells (Jose et al., 2014), potentially increasing their pro-angiogenic efficacy and capacity for tissue repair (Rustad et al., 2012; Hoffman et al., 2013). Together, the numerous and diverse effects of this peptide make it an intriguing drug for use in pro-angiogenic, wound repair, and tissue engineering applications. "
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    ABSTRACT: Insufficient vascularization currently limits the size and complexity for all tissue engineering approaches. Additionally, increasing or re-initiating blood flow is the first step toward restoration of ischemic tissue homeostasis. However, no FDA-approved pro-angiogenic treatments exist, despite the many pre-clinical approaches that have been developed. The relatively small size of peptides gives advantages over protein-based treatments, specifically with respect to synthesis and stability. While many pro-angiogenic peptides have been identified and shown promising results in vitro and in vivo, the majority of biomaterials developed for pro-angiogenic drug delivery focus on protein delivery. This narrow focus limits pro-angiogenic therapeutics as peptides, similar to proteins, suffer from poor pharmacokinetics in vivo, necessitating the development of controlled release systems. This review discusses pro-angiogenic peptides and the biomaterials delivery systems that have been developed, or that could easily be adapted for peptide delivery, with a particular focus on depot-based delivery systems.
    Frontiers in Bioengineering and Biotechnology 07/2015; 3(102). DOI:10.3389/fbioe.2015.00102
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    • "The MSCs delivery method is also very important and some authors used subcutaneous injection, systemic injection, intradermal injection and topical applications or combinations of these routes 17, 18. The clinical effectiveness of MSCs-based therapy is dependent on the number of cells delivered and survival, so it is important to optimize the delivery procedure. "
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    ABSTRACT: The healing process of the skin is a dynamic procedure mediated through a complex feedback of growth factors secreted by a variety of cells types. Despite the most recent advances in wound healing management and surgical procedures, these techniques still fail up to 50%, so cellular therapies involving mesenchymal stem cells (MSCs) are nowadays a promising treatment of skin ulcers which are a cause of high morbidity. The MSCs modulate the inflammatory local response and induce cell replacing, by a paracrine mode of action, being an important cell therapy for the impaired wound healing. The local application of human MSCs (hMSCs) isolated from the umbilical cord Wharton’s jelly together with a poly(vinyl alcohol) hydrogel (PVA) membrane, was tested to promote wound healing in two dogs that were referred for clinical examination at UPVET Hospital, showing non-healing large skin lesions by the standard treatments. The wounds were infiltrated with 1000 cells/μl hMSCs in a total volume of 100 μl per cm2 of lesion area. A PVA membrane was applied to completely cover the wound to prevent its dehydration. Both animals after the treatment demonstrated a significant progress in skin regeneration with decreased extent of ulcerated areas confirmed by histological analysis. The use of Wharton’s jelly MSCs associated with a PVA membrane showed promising clinical results for future application in the treatment of chronic wounds in companion animals and humans.
    International journal of medical sciences 07/2014; 11(10):979-987. DOI:10.7150/ijms.9139 · 2.00 Impact Factor
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    • "WT or DM2 ASCs (8 × 105) (cultured not more than two passages) were suspended in 250 μL of growth factor-reduced Matrigel (BD Biosciences) and injected in a subcutaneous fashion on the dorsum of WT mice (n = 4). Plugs were harvested at day 10, and 7-μm-thick frozen sections were immunohistochemically stained for the commonly used vascular marker platelet/endothelial cell adhesion molecule 1 (PECAM1/CD31, a transmembrane glycoprotein expressed on the surface of platelets, endothelial cells, and subsets of hematopoietic cells but particularly concentrated at the intercellular junctions of endothelial cells), followed by ImageJ (National Institutes of Health, Bethesda, MD, USA) quantification [7,21]. "
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    ABSTRACT: Introduction Pathophysiologic changes associated with diabetes impair new blood vessel formation and wound healing. Mesenchymal stem cells derived from adipose tissue (ASCs) have been used clinically to promote healing, although it remains unclear whether diabetes impairs their functional and therapeutic capacity. Methods In this study, we examined the impact of diabetes on the murine ASC niche as well as on the potential of isolated cells to promote neovascularization in vitro and in vivo. A novel single-cell analytical approach was used to interrogate ASC heterogeneity and subpopulation dynamics in this pathologic setting. Results Our results demonstrate that diabetes alters the ASC niche in situ and that diabetic ASCs are compromised in their ability to establish a vascular network both in vitro and in vivo. Moreover, these diabetic cells were ineffective in promoting soft tissue neovascularization and wound healing. Single-cell transcriptional analysis identified a subpopulation of cells which was diminished in both type 1 and type 2 models of diabetes. These cells were characterized by the high expression of genes known to be important for new blood vessel growth. Conclusions Perturbations in specific cellular subpopulations, visible only on a single-cell level, represent a previously unreported mechanism for the dysfunction of diabetic ASCs. These data suggest that the utility of autologous ASCs for cell-based therapies in patients with diabetes may be limited and that interventions to improve cell function before application are warranted.
    Stem Cell Research & Therapy 06/2014; 5(3):79. DOI:10.1186/scrt468 · 3.37 Impact Factor
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