Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad 500007, Telangana, India.
Academy of Scientific and Innovative Research, Ghaziabad 201002, Uttar Pradesh, India.
ACS Appl Mater Interfaces. 2024 Jul 24;16(29):37418-37434. doi: 10.1021/acsami.4c02633. Epub 2024 Jul 9.
The re-epithelialization process gets severely dysregulated in chronic nonhealing diabetic foot ulcers/wounds. Keratinocyte growth factor (KGF or FGF-7) is the major modulator of the re-epithelialization process, which regulates the physiological phenotypes of cutaneous keratinocytes. The existing therapeutic strategies of growth factor administration have several limitations. To overcome these, we have designed a KGF-mimetic peptide (KGFp, 13mer) based on the receptor interaction sites in murine KGF. KGFp enhanced migration and transdifferentiation of mouse bone marrow-derived MSCs toward keratinocyte-like cells (KLCs). A significant increase in the expression of skin-specific markers (28.5-fold), (14.6-fold), (26.1-fold), (187.7-fold), and epithelial markers (23.3-fold) and (64.2-fold) was associated with the activation of ERK1/2 and STAT3 molecular signaling in the KLCs. Further, to enhance the stability of KGFp in the wound microenvironment, it was conjugated to biocompatible 3D porous polymer scaffolds without compromising its active binding sites followed by chemical characterization using Fourier transform infrared spectroscopy, field-emission scanning electron microscopy, dynamic mechanical analysis, and thermogravimetry. evaluation of the KGFp-conjugated 3D polymer scaffolds revealed its potential for transdifferentiation of MSCs into KLCs. Transplantation of allogeneic MSC using KGFp-conjugated 3D polymer scaffolds in chronic nonhealing type 2 diabetic wounds ( transgenic, 50-52 weeks old male mice) significantly enhanced re-epithelialization-mediated wound closure rate (79.3%) as compared to the control groups (Untransplanted -22.4%, MSC-3D polymer scaffold -38.5%). Thus, KGFp-conjugated 3D porous polymer scaffolds drive the fate of the MSCs toward keratinocytes that may serve as potential stem cell delivery platform technology for tissue engineering and transplantation.
在慢性难愈性糖尿病足溃疡/创面中，再上皮化过程严重失调。角质细胞生长因子（KGF 或 FGF-7）是再上皮化过程的主要调节剂，调节皮肤角质形成细胞的生理表型。现有的生长因子给药治疗策略存在多种局限性。为了克服这些局限性，我们基于鼠 KGF 的受体相互作用位点设计了一种 KGF 模拟肽（KGFp，13 肽）。KGFp 增强了骨髓间充质干细胞向角质细胞样细胞（KLC）的迁移和转分化。KLC 中 ERK1/2 和 STAT3 分子信号的激活与皮肤特异性标志物（28.5 倍）、（14.6 倍）、（26.1 倍）、（187.7 倍）和上皮标志物（23.3 倍）和（64.2 倍）的表达显著增加有关。进一步，为了增强 KGFp 在创面微环境中的稳定性，将其与生物相容性的 3D 多孔聚合物支架偶联，而不影响其活性结合位点，然后使用傅里叶变换红外光谱、场发射扫描电子显微镜、动态力学分析和热重分析进行化学表征。KGFp 偶联 3D 聚合物支架的评估显示其具有将间充质干细胞向 KLC 转分化的潜力。在慢性难愈性 2 型糖尿病创面（转基因，50-52 周龄雄性小鼠）中，使用 KGFp 偶联 3D 聚合物支架移植同种异体 MSC 可显著提高再上皮化介导的创面闭合率（79.3%），而对照组（未移植-22.4%，MSC-3D 聚合物支架-38.5%）。因此，KGFp 偶联 3D 多孔聚合物支架促使 MSC 向角质细胞分化，这可能成为组织工程和移植的潜在干细胞递送平台技术。
