Tunable Hydrogels Derived from Genetically Engineered Extracellular Matrix Accelerate Diabetic Wound Healing

Morris, Aaron H.; Hudson, Lee; Xing, Hao; Stamer, Danielle; Tan, Marina; Kyriakides, Themis R.

doi:10.1021/acsami.8b08920

Cited by 35 publications

(35 citation statements)

References 56 publications

(88 reference statements)

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“…THBS2 knockdown enhanced cell proliferation but reduced cell apoptosis after HG treatment, suggesting that silencing THBS2 might protect HK-2 cells from HG injury. This is consistent with a report that showed THBS2-knockdown hydrogels composed of solubilized decellularized ECM notably improved diabetic wound healing [40]. Furthermore, through rescue experiments, we also proved that knockdown of THBS2 attenuated the HG-induced tubule cells injury caused by the miR-1228 inhibitor.…”

Section: Discussionsupporting

confidence: 92%

MicroRNA 1228 Mediates the Viability of High Glucose-Cultured Renal Tubule Cells through Targeting Thrombospondin 2 and PI3K/AKT Signaling Pathway

Mo¹,

Fu²,

Hu³

et al. 2021

Kidney Blood Press Res

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Aim: The present study aimed to elucidate the potential function of microRNA 1228 (miR-1228) on the high glucose (HG)-damaged human renal proximal tubule cells (HK-2) and the underlying mechanism. Methods: The datasets GSE47185 and GSE51674 were downloaded from the Gene Expression Omnibus database for mining differently expressed mRNAs and miRNAs, respectively. Bioinformatics online tools were applied to predict the binding sites between miR-1228 and thrombospondin 2 (THBS2), which was confirmed by dual-luciferase assay. Real-time quantitative polymerase chain reaction was used to detect the mRNA level of miR-1228/THBS2. Western blot was used to detect the protein level of THBS2 and the PI3K/AKT signaling pathway-associated markers. HK-2 cells were cultured in HG (30 mM) to mimic hyperglycemia. Cell counting kit 8 and flow cytometry assays were utilized to determine the cell proliferation and apoptosis. Results: The expression of THBS2 was significantly upregulated in diabetic nephropathy (DN) based on bioinformatics tools and identified as a direct target of miR-1228. miR-1228 was downregulated in DN and HG-damaged HK-2 cells. HG notably reduced HK-2 cell proliferation. This negative effect was attenuated by transfecting with an miR-1228 mimic and aggravated by transfecting with an miR-1228 inhibitor. However, under basal condition, there was no significant effect on the HK-2 cell proliferation among blank control, mimic, and inhibitor groups. Overexpression of THBS2 abolished the elevating effect of the miR-1228 mimic on the HG-damaged HK-2 cell proliferation, while restored the inhibitory effects of the miR-1228 mimic on the cell apoptosis. On the contrary, the suppressive effects on the proliferation and the enhancive effects on the apoptosis by silencing miR-1228 in HK-2 cells stimulated with HG can be weakened by recommendation of THBS2 small interference RNAs. Furthermore, we also found that HG significantly enhanced the phosphorylation levels of PI3K and AKT. In terms of overexpression and knockdown experiments, Western blot analysis further revealed that miR-1228 inhibited the activation of the PI3K/AKT signaling pathway in HG-damaged HK-2 cells by regulating THBS2. Conclusion: The findings illustrated that miR-1228 improved survivability and inhibited apoptosis in HK-2 cells stimulated with HG partly by restraining the activation of the PI3K/AKT signaling pathway.

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Section: Discussionsupporting

confidence: 92%

MicroRNA 1228 Mediates the Viability of High Glucose-Cultured Renal Tubule Cells through Targeting Thrombospondin 2 and PI3K/AKT Signaling Pathway

Mo¹,

Fu²,

Hu³

et al. 2021

Kidney Blood Press Res

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“…Acellular matrices can be isolated from full skins ( Hsieh et al, 2020 ; Lin et al, 2020 ) and adipose tissues ( Dongen et al, 2019 ; Tan et al, 2019 ; Pu et al, 2020 ). In addition, acellular matrices are genetically tunable to adjust cell invasion through thrombospondin-2 knockout resulted in faster wound healing ( Morris et al, 2018 ).…”

Section: Fabrication Of Hydrogel For Wound Healingmentioning

confidence: 99%

Biomimetic Hydrogels to Promote Wound Healing

Fan

Saha

Hanjaya‐Putra

2021

Front. Bioeng. Biotechnol.

103

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Wound healing is a common physiological process which consists of a sequence of molecular and cellular events that occur following the onset of a tissue lesion in order to reconstitute barrier between body and external environment. The inherent properties of hydrogels allow the damaged tissue to heal by supporting a hydrated environment which has long been explored in wound management to aid in autolytic debridement. However, chronic non-healing wounds require added therapeutic features that can be achieved by incorporation of biomolecules and supporting cells to promote faster and better healing outcomes. In recent decades, numerous hydrogels have been developed and modified to match the time scale for distinct stages of wound healing. This review will discuss the effects of various types of hydrogels on wound pathophysiology, as well as the ideal characteristics of hydrogels for wound healing, crosslinking mechanism, fabrication techniques and design considerations of hydrogel engineering. Finally, several challenges related to adopting hydrogels to promote wound healing and future perspectives are discussed.

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“…Full-thickness, nonsplinted excisional wounds were generated as previously described (6,(12)(13)(14). Briefly, mice were anesthetized and depilated, and two 6-mm wounds were created with a biopsy punch (Acuderm) and left uncovered.…”

Section: Woundsmentioning

confidence: 99%

“…Healing in DKO mice was evaluated through a fullthickness excisional wound model (12,13). DKO mice exhibited improved healing, with more rapid reduction of wound size (Fig.…”

Section: Tsp2 Is Elevated In Diabetesmentioning

confidence: 99%

Elevated Thrombospondin 2 Contributes to Delayed Wound Healing in Diabetes

et al. 2019

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Impaired wound healing is a major complication of diabetes and can lead to the development of chronic wounds in a significant portion of diabetes patients. Despite the risks posed by impaired healing, treatment strategies for diabetic wounds remain limited due to an incomplete understanding of the underlying pathological mechanisms. Previous studies have demonstrated that overexpression of thrombospondin‐2 (TSP2), a matricellular protein released after tissue injury, is associated with significant delays in dermal healing in various mouse models. Consistently, wounds lacking TSP2 (TSP2 KO) heal faster than wounds in wild‐type mice or mice with elevated TSP2. Thus, the present study aimed to examine the role of TSP2 in delayed healing in diabetes. First, we evaluated TSP2 expression in human wounds, and found that TSP2 is elevated in wounds from diabetes patients. Then, to determine TSP2's contribution to impaired healing in diabetes, we developed a novel diabetic TSP2 KO mouse model. Though these db/db TSP2 KO mice develop obesity and hyperglycemia comparable to db/db mice, db/db TSP2 KO mice exhibit significantly improved healing. Moreover, primary fibroblasts isolated from db/db TSP2 KO mice exhibit improved migration, providing mechanistic insight into the accelerated healing in these mice. We also studied TSP2 expression in fibroblasts, the major source of TSP2 in the wound, to explore the mechanisms leading to its overexpression in diabetes. Our results showed that TSP2 expression is increased in hyperglycemia, through increased activation of the hexosamine biosynthesis pathway and subsequent O‐GlcNAc modification of transcriptional elements. Overall, the results of this study indicate for the first time that: 1) TSP2 expression is elevated in diabetes and hyperglycemia and 2) TSP2 contributes to impaired healing in diabetes. These results represent a novel role for TSP2 in diabetes complications and a novel target for improving wound healing in diabetes. Support or Funding Information NIH HL107205, NIH GM 072194, Gruber Science Fellowship This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Tunable Hydrogels Derived from Genetically Engineered Extracellular Matrix Accelerate Diabetic Wound Healing

Cited by 35 publications

References 56 publications

MicroRNA 1228 Mediates the Viability of High Glucose-Cultured Renal Tubule Cells through Targeting Thrombospondin 2 and PI3K/AKT Signaling Pathway

MicroRNA 1228 Mediates the Viability of High Glucose-Cultured Renal Tubule Cells through Targeting Thrombospondin 2 and PI3K/AKT Signaling Pathway

Biomimetic Hydrogels to Promote Wound Healing

Elevated Thrombospondin 2 Contributes to Delayed Wound Healing in Diabetes

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