Enhancing the function of CD34(+) cells by targeting plasminogen activator inhibitor-1.
Enhancing the function of CD34(+) cells by targeting plasminogen activator inhibitor-1.
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DOI：
10.1371/journal.pone.0079067
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Grant MB
中科院分区：
文献类型：
--
作者：
Hazra S;Stepps V;Bhatwadekar AD;Caballero S;Boulton ME;Higgins PJ;Nikonova EV;Pepine CJ;Thut C;Finney EM;Stone DJ;Bartelmez SH;Grant MB
此前，我们表明短暂抑制 TGF-β1 可以纠正糖尿病引起的 CD34+ 细胞功能障碍的关键方面。在本报告中，我们研究了纤溶酶原激活剂抑制剂-1 (PAI-1) 瞬时抑制的效果，PAI-1 是 TGF-β1 激活的主要基因靶标。通过基因阵列研究，我们检查了从一组长期患有糖尿病的个体中分离出的 CD34+ 细胞，尽管血糖控制不佳，但没有出现微血管并发症，结果发现，与年龄、性别和血糖控制程度相匹配的患有微血管并发症的糖尿病个体相比，这些细胞表现出 TGF-β1 和 PAI-1 的转录物减少。患有微血管并发症的糖尿病受试者的 CD34+ 细胞始终表现出比年龄匹配的非糖尿病对照更高的 PAI-1 mRNA。 TGF-β1 磷酸二酰胺吗啉寡 (PMO) 减少糖尿病 (p<0.01) 和非糖尿病 (p=0.05) CD34+ 细胞中的 PAI-1 mRNA。为了减少人 CD34+ 细胞中的 PAI-1，我们利用了 PAI-1 siRNA、表达 PAI-1 shRNA 的慢病毒或 PAI-1 PMO。我们发现，抑制 PAI-1 可能通过增加 PI3(K) 活性和增加 cGMP 产量，促进体外 CD34+ 细胞增殖和迁移。使用小鼠视网膜缺血再灌注损伤模型，我们观察到与对照 PMO 处理的细胞相比，PAI-1-PMO 处理后糖尿病 CD34+ 细胞向受损的无细胞视网膜毛细血管的募集更多。靶向 PAI-1 为恢复有缺陷的糖尿病祖细胞的血管修复功能提供了一种有前途的治疗策略。
Previously, we showed that transient inhibition of TGF- β1 resulted in correction of key aspects of diabetes-induced CD34+ cell dysfunction. In this report, we examine the effect of transient inhibition of plasminogen activator inhibitor-1 (PAI-1), a major gene target of TGF-β1 activation. Using gene array studies, we examined CD34+ cells isolated from a cohort of longstanding diabetic individuals, free of microvascular complications despite suboptimal glycemic control, and found that the cells exhibited reduced transcripts of both TGF-β1 and PAI-1 compared to age, sex, and degree of glycemic control-matched diabetic individuals with microvascular complications. CD34+ cells from diabetic subjects with microvascular complications consistently exhibited higher PAI-1 mRNA than age-matched non-diabetic controls. TGF- β1 phosphorodiamidate morpholino oligo (PMO) reduced PAI-1 mRNA in diabetic (p<0.01) and non-diabetic (p=0.05) CD34+ cells. To reduce PAI-1 in human CD34+ cells, we utilized PAI-1 siRNA, lentivirus expressing PAI-1 shRNA or PAI-1 PMO. We found that inhibition of PAI-1 promoted CD34+ cell proliferation and migration in vitro, likely through increased PI3(K) activity and increased cGMP production. Using a retinal ischemia reperfusion injury model in mice, we observed that recruitment of diabetic CD34+ cells to injured acellular retinal capillaries was greater after PAI-1-PMO treatment compared with control PMO-treated cells. Targeting PAI-1 offers a promising therapeutic strategy for restoring vascular reparative function in defective diabetic progenitors.
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影响因子：
39.3
作者：
Fadini, Gian Paolo;Vigili de Kreutzenberg, Saula;Avogaro, Angelo
通讯作者：
Avogaro, Angelo
影响因子：
7.7
作者：
Caballero, Sergio;Sengupta, Nilanjana;Grant, Maria B.
通讯作者：
Grant, Maria B.
影响因子：
15.9
作者：
Gallagher, Katherine A.;Liu, Zhao-Jun;Velazquez, Omaida C.
通讯作者：
Velazquez, Omaida C.
影响因子：
82.9
作者：
Aicher, A;Heeschen, C;Dimmeler, S
通讯作者：
Dimmeler, S
DOI：
10.1084/jem.20090889
发表时间：
2009-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Busik JV;Tikhonenko M;Bhatwadekar A;Opreanu M;Yakubova N;Caballero S;Player D;Nakagawa T;Afzal A;Kielczewski J;Sochacki A;Hasty S;Li Calzi S;Kim S;Duclas SK;Segal MS;Guberski DL;Esselman WJ;Boulton ME;Grant MB
通讯作者：
Grant MB