Defective recruitment, survival and proliferation of bone marrow-derived progenitor cells at sites of delayed diabetic wound healing in mice
Defective recruitment, survival and proliferation of bone marrow-derived progenitor cells at sites of delayed diabetic wound healing in mice
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DOI：
10.1007/s00125-010-2007-2
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发表时间：
2011-04-01
期刊：
影响因子：
8.2
通讯作者：
Fadini, G. P.
中科院分区：
文献类型：
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作者：
Albiero, M.;Menegazzo, L.;Fadini, G. P.
骨髓来源的内皮祖细胞(EPC)促进组织愈合和血管生成，而EPC生物学改变可能有利于糖尿病并发症。我们验证了糖尿病损害骨髓来源细胞在伤口愈合部位的作用的假设。在C57BL/6小鼠诱导糖尿病后4周，建立了后肢皮肤伤口，并通过数字成像和组织学进行监测。用流式细胞仪检测伤前、伤后循环内皮祖细胞的数量。在单独的实验中，在诱导糖尿病之前，将产生绿色荧光蛋白(GFP)的C57BL/6小鼠的骨髓移植到去髓的野生型小鼠。我们对组织中GFP(+)细胞的增殖、凋亡和内皮分化进行了定量。通过校正每个时间点组织中GFP(+)细胞的基础水平、细胞凋亡率和增殖率来估计GFP(+)细胞的净募集。糖尿病延迟创面愈合，肉芽组织厚度和血管减少，细胞凋亡率增加。4周糖尿病和/或皮肤损伤不影响循环内皮祖细胞水平。糖尿病小鼠肉芽组织中的骨髓来源内皮祖细胞(GFP(+)、VWF(+)[von Willebrand因子]细胞)与对照组相比显著减少。骨髓来源的GFP(+)细胞在糖尿病创面组织中较非糖尿病创面组织中表现出更多的凋亡和更少的增殖。糖尿病小鼠创伤后第1天，估计骨髓来源的GFP(+)细胞的净募集减少。糖尿病延迟的伤口愈合与骨髓来源的祖细胞的缺陷募集、存活和增殖有关。旨在恢复EPC归巢和存活的局部治疗可能会改善糖尿病的组织愈合。
Bone marrow (BM)-derived endothelial progenitor cells (EPC) promote tissue healing and angiogenesis, whereas altered EPC biology may favour diabetic complications. We tested the hypothesis that diabetes impairs the contribution of BM-derived cells at sites of wound healing.Four weeks after induction of diabetes in C57BL/6 mice, hindlimb skin wounds were created and monitored by digital imaging and histology. Circulating EPCs were quantified by flow cytometry before and after wounding. In separate experiments, bone marrow from C57BL/6 mice constitutively producing green fluorescent protein (GFP) was transplanted into myeloablated wild-type mice before induction of diabetes. We quantified proliferation, apoptosis and endothelial differentiation of tissue GFP(+) cells. Net recruitment of GFP(+) cells was estimated by correcting the number of tissue GFP(+) cells at each time point for basal levels, apoptosis and proliferation rates.Diabetes delayed wound healing, with reduced granulation tissue thickness and vascularity, and increased apoptosis. Circulating EPC levels were not modified by 4 week diabetes and/or skin wounding. BM-derived EPCs (GFP(+)vWf(+) [von Willebrand factor] cells) within the granulation tissue were significantly reduced in diabetic compared with control mice. BM-derived GFP(+) cells showed increased apoptosis and decreased proliferation in diabetic versus non-diabetic wound tissues. Estimated net recruitment of BM-derived GFP(+) cells was reduced on day 1 after wounding in diabetic mice.Diabetic-delayed wound healing was associated with defective recruitment, survival and proliferation of BM-derived progenitor cells. Local treatments aimed at restoring EPC homing and survival might improve tissue healing in diabetes.