Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs.
Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs.
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DOI：
10.1097/sla.0000000000005949
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发表时间：
2023-09-01
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
在这里，我们报告了一种新的方法，以增加治疗潜力的间充质干/基质细胞（MSC）的缺血性伤口愈合。我们测试了用E-选择素修饰的MSC的生物学效应，E-选择素是一种能够诱导出生后新生血管形成的细胞粘附分子，在小鼠转译模型上。对于慢性威胁肢体缺血的患者，组织缺损显著增加了肢体截肢的风险。基于MSC的治疗方法在伤口愈合和治疗性血管生成方面具有重大前景，但未经修饰的MSC仅表现出有限的益处。用E-选择素-绿色荧光蛋白（GFP）/AAV-DJ或GFP/AAV-DJ（对照）转导从FVB/ROSA 26 SormTmG供体小鼠收获的骨髓细胞。在受体FVB小鼠的股动脉结扎后，通过在同侧肢体中的4 mm打孔活检产生缺血性伤口，随后注射磷酸盐缓冲盐水或1 × 106供体MSCGFP或MSCE-selectin-GFP。术后7天每天监测伤口闭合情况，收集组织进行分子和组织学分析以及免疫荧光。全身DiI灌注和共聚焦显微镜用于评估伤口血管生成。未修饰的MSC不表达E-选择素，MSCE-selectin-GFP获得更强的MSC表型，同时保持三系分化和集落形成能力。与MSCGFP和磷酸盐缓冲盐水治疗相比，MSCE-选择素-GFP治疗加速伤口愈合。移植的MSCE-选择素-GFP在术后第7天在伤口中表现出更强的存活和活力。用MSCE-selectin-GFP处理的缺血性伤口表现出更丰富的胶原沉积和增强的血管生成反应。我们建立了一种新的方法，以加强再生和促血管生成能力的MSC修饰E-选择素/腺相关病毒。这种创新疗法具有作为未来临床研究平台的潜力。
Here, we report a new method to increase the therapeutic potential of mesenchymal stem/stromal cells (MSCs) for ischemic wound healing. We tested biological effects of MSCs modified with E-selectin, a cell adhesion molecule capable of inducing postnatal neovascularization, on a translational murine model. Tissue loss significantly worsens the risk of extremity amputation for patients with chronic limb-threatening ischemia. MSC-based therapeutics hold major promise for wound healing and therapeutic angiogenesis, but unmodified MSCs demonstrate only modest benefits. Bone marrow cells harvested from FVB/ROSA26SormTmG donor mice were transduced with E-selectin-green fluorescent protein (GFP)/AAV-DJ or GFP/AAV-DJ (control). Ischemic wounds were created via a 4 mm punch biopsy in the ipsilateral limb after femoral artery ligation in recipient FVB mice and subsequently injected with phosphate-buffered saline or 1×106 donor MSCGFP or MSCE-selectin-GFP. Wound closure was monitored daily for 7 postoperative days, and tissues were harvested for molecular and histologic analysis and immunofluorescence. Whole-body DiI perfusion and confocal microscopy were utilized to evaluate wound angiogenesis. Unmodified MSCs do not express E-selectin, and MSCE-selectin-GFP gain stronger MSC phenotype yet maintain trilineage differentiation and colony-forming capability. MSCE-selectin-GFP therapy accelerates wound healing compared with MSCGFP and phosphate-buffered saline treatment. Engrafted MSCE-selectin-GFP manifest stronger survival and viability in wounds at postoperative day 7. Ischemic wounds treated with MSCE-selectin-GFP exhibit more abundant collagen deposition and enhanced angiogenic response. We establish a novel method to potentiate regenerative and proangiogenic capability of MSCs by modification with E-selectin/adeno-associated virus. This innovative therapy carries the potential as a platform worthy of future clinical studies.
影响因子：
3.7
作者：
Rosu-Myles M;She YM;Fair J;Muradia G;Mehic J;Menendez P;Prasad SS;Cyr TD
通讯作者：
Cyr TD