Three-Dimensional Human Tissue Models That Incorporate Diabetic Foot Ulcer-Derived Fibroblasts Mimic <i>In Vivo</i> Features of Chronic Wounds

Maione, Anna G.; Brudno, Yevgeny; Stojadinović, Olivera; Park, Lara K.; Smith, Avi; Tellechea, Ana; Leal, Ermelindo C.; Kearney, Cathal J.; Veves, Aristidis; Tomic‐Canic, Marjana; Mooney, David J.; Garlick, Jonathan A.

doi:10.1089/ten.tec.2014.0414

Cited by 76 publications

(82 citation statements)

References 37 publications

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“…Future studies will allow us to determine if expression of genes critical to wound repair, angiogenesis, and ECM assembly (Maione et al, 2015;Park et al, 2014), which may be abnormal in DFUs, could be normalized after reprogramming to iPSC and subsequent differentiation to fibroblast lineage.…”

Section: Discussionmentioning

confidence: 99%

“…iPSCs were derived using the CytoTune Ò -iPS 2.0 Sendai Reprogramming Kit (Life Technologies) from three fibroblast cell types, including DFU-derived fibroblasts, nonulcerated site-matched DFFs, and nonulcerated site-matched NFFs that were previously characterized (Maione et al, 2015;Park et al, 2014) (Fig. 1A).…”

Section: Dfu-derived Fibroblasts Can Be Reprogrammed To Ipscsmentioning

confidence: 99%

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Generation of Induced Pluripotent Stem Cells from Diabetic Foot Ulcer Fibroblasts Using a Nonintegrative Sendai Virus

Gerami‐Naini

Smith

Maione

et al. 2016

Cellular Reprogramming

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Diabetic foot ulcers (DFUs) are nonhealing chronic wounds that are a serious complication of diabetes. Since induced pluripotent stem cells (iPSCs) may offer a potent source of autologous cells to heal these wounds, we studied if repair-deficient fibroblasts, derived from DFU patients and age-and site-matched control fibroblasts, could be reprogrammed to iPSCs. To establish this, we used Sendai virus to successfully reprogram six primary fibroblast cell lines derived from ulcerated skin of two DFU patients (DFU8, DFU25), nonulcerated foot skin from two diabetic patients (DFF24, DFF9), and healthy foot skin from two nondiabetic patients (NFF12, NFF14). We confirmed reprogramming to a pluripotent state through three independent criteria: immunofluorescent staining for SSEA-4 and TRA-1-81, formation of embryoid bodies with differentiation potential to all three embryonic germ layers in vitro, and formation of teratomas in vivo. All iPSC lines showed normal karyotypes and typical, nonmethylated CpG sites for OCT4 and NANOG. iPSCs derived from DFUs were similar to those derived from site-matched nonulcerated skin from both diabetic and nondiabetic patients. These results have established for the first time that multiple, DFU-derived fibroblast cell lines can be reprogrammed with efficiencies similar to control fibroblasts, thus demonstrating their utility for future regenerative therapy of DFUs.

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Section: Discussionmentioning

confidence: 99%

Section: Dfu-derived Fibroblasts Can Be Reprogrammed To Ipscsmentioning

confidence: 99%

Generation of Induced Pluripotent Stem Cells from Diabetic Foot Ulcer Fibroblasts Using a Nonintegrative Sendai Virus

Gerami‐Naini

Smith

Maione

et al. 2016

Cellular Reprogramming

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“…Commercially available skin constructs are typically composed of only keratinocytes and fibroblasts, and have limitations including poor viability and integration, essentially leading to formation of a non-functional scarred skin [1, 2] .…”

Section: Introductionmentioning

confidence: 99%

Human Skin Constructs with Spatially Controlled Vasculature Using Primary and iPSC‐Derived Endothelial Cells

Abaci

Guo

Coffman

et al. 2016

Adv Healthcare Materials

205

171

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Vascularization of engineered human skin constructs is crucial for recapitulation of systemic drug delivery and for their long-term survival, functionality, and viable engraftment. In this study, we used the latest microfabrication techniques and established a novel bioengineering approach to micropattern spatially-controlled and perfusable vascular networks in 3D human skin equivalents using both primary and induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs). Using 3D printing technology, we were able to control the geometry of the micropatterned vascular networks. We verified that vascularized human skin equivalents (vHSEs) can form a robust epidermis and establish an endothelial barrier function, which allows for the recapitulation of both topical and systemic delivery of drugs. In addition, we examined the therapeutic potential of vHSEs for cutaneous wounds on immunodeficient mice and demonstrated that vHSEs can both promote and guide neovascularization during wound healing. Overall, this innovative bioengineering approach could enable in vitro evaluation of topical and systemic drug delivery, as well as improve the potential of engineered skin constructs to be used as a potential therapeutic option for the treatment of cutaneous wounds.

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“…It is not known whether this "metabolic memory" in gene expression would persist in iPSCs reprogrammed from fibroblasts derived from patients with diabetes or from DFUs. Thus, it would be helpful to understand whether the impaired woundrepair functions found in DFU-derived fibroblasts (8,9,31) would be modified after reprogramming to iPSCs and subsequent differentiation to fibroblasts.…”

mentioning

confidence: 99%

Differentiation of diabetic foot ulcer–derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes

et al. 2018

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Diabetic foot ulcers (DFUs) are a major complication of diabetes, and there is a critical need to develop novel cell- and tissue-based therapies to treat these chronic wounds. Induced pluripotent stem cells (iPSCs) offer a replenishing source of allogeneic and autologous cell types that may be beneficial to improve DFU wound-healing outcomes. However, the biologic potential of iPSC-derived cells to treat DFUs has not, to our knowledge, been investigated. Toward that goal, we have performed detailed characterization of iPSC-derived fibroblasts from both diabetic and nondiabetic patients. Significantly, gene array and functional analyses reveal that iPSC-derived fibroblasts from both patients with and those without diabetes are more similar to each other than were the primary cells from which they were derived. iPSC-derived fibroblasts showed improved migratory properties in 2-dimensional culture. iPSC-derived fibroblasts from DFUs displayed a unique biochemical composition and morphology when grown as 3-dimensional (3D), self-assembled extracellular matrix tissues, which were distinct from tissues fabricated using the parental DFU fibroblasts from which they were reprogrammed. In vivo transplantation of 3D tissues with iPSC-derived fibroblasts showed they persisted in the wound and facilitated diabetic wound closure compared with primary DFU fibroblasts. Taken together, our findings support the potential application of these iPSC-derived fibroblasts and 3D tissues to improve wound healing.-Kashpur, O., Smith, A., Gerami-Naini, B., Maione, A. G., Calabrese, R., Tellechea, A., Theocharidis, G., Liang, L., Pastar, I., Tomic-Canic, M., Mooney, D., Veves, A., Garlick, J. A. Differentiation of diabetic foot ulcer-derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes.

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Three-Dimensional Human Tissue Models That Incorporate Diabetic Foot Ulcer-Derived Fibroblasts Mimic In Vivo Features of Chronic Wounds

Cited by 76 publications

References 37 publications

Generation of Induced Pluripotent Stem Cells from Diabetic Foot Ulcer Fibroblasts Using a Nonintegrative Sendai Virus

Generation of Induced Pluripotent Stem Cells from Diabetic Foot Ulcer Fibroblasts Using a Nonintegrative Sendai Virus

Human Skin Constructs with Spatially Controlled Vasculature Using Primary and iPSC‐Derived Endothelial Cells

Differentiation of diabetic foot ulcer–derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes

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