No influence on tumor growth by intramuscular injection of adipose-derived regenerative cells: safety evaluation of therapeutic angiogenesis with cell therapy
No influence on tumor growth by intramuscular injection of adipose-derived regenerative cells: safety evaluation of therapeutic angiogenesis with cell therapy
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DOI：
10.1152/ajpheart.00564.2020
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发表时间：
2021-01-01
影响因子：
4.8
通讯作者：
Murohara, Toyoaki
中科院分区：
文献类型：
--
作者：
Suzuki, Junya;Shimizu, Yuuki;Murohara, Toyoaki
自体干/祖细胞治疗性血管生成是治疗严重缺血性疾病的一种有前途的新策略。迄今为止，利用自体脂肪源再生细胞（ADRC）的人体临床试验尚未报告与治疗相关的严重不良反应。然而，关于使用ADRC的血管生成疗法治疗缺血性疾病是否会促进与体内肿瘤相关的不利血管生成，仍然存在很大的知识差距。在此，我们使用小鼠后肢缺血（HLI）和同时远程肿瘤植入模型来解决这个临床问题。在缺血性手术前1天，在C57 BL/6 J背景野生型小鼠的背部注射鼠B16 F10黑素瘤细胞。对这些小鼠进行手术单侧后肢缺血，然后在第二天将ADRC植入或PBS注射到后肢缺血肌肉中。肌内植入ADRCs增强了后肢组织毛细血管密度和血流，通过激光多普勒血流灌注分析进行了检查。然而，与PBS组相比，这种使用ADRCs治疗缺血肢体的治疗方案并不影响远端黑色素瘤的生长，也不影响其供血动脉、血管生成和淋巴管的密度。此外，在任何小鼠中均未检测到远处转移，与组无关。总之，ADRC的局部植入促进了后肢组织缺血后的血管生成，而不会促进远端肿瘤生长和相关的血管/淋巴管生成。治疗性血管生成的缺血后肢使用ADRCs似乎是安全的远程肿瘤growth.NEW &值得注意的是在这项研究中，我们证明，局部注射ADRCs可以促进血管生成，在组织缺血，而不促进远程肿瘤生长的小鼠模型。我们的研究结果表明，治疗血管生成缺血后肢使用ADRC似乎是安全的远程肿瘤生长。
Therapeutic angiogenesis with autologous stem/progenitor cells is a promising novel strategy for treatment of severe ischemic diseases. Human clinical trials utilizing autologous adipose-derived regenerative cells (ADRCs) have not reported treatment-related critical adverse effects thus far. However, there is still a large knowledge gap regarding whether treatment of ischemic diseases with angiogenic therapy using ADRCs would promote unfavorable angiogenesis associated with tumors in vivo. Herein, we addressed this clinical question using a mouse hindlimb ischemia (HLI) and simultaneous remote tumor implantation model. C57BL/6J background wild-type mice were injected with murine B16F10 melanoma cells on their back, 1 day before ischemic surgery. These mice were subjected to surgical unilateral hindlimb ischemia, followed by ADRC implantation or PBS injection into the hindlimb ischemic muscles on the next day. Intramuscular implantation of ADRCs enhanced tissue capillary density and blood flow examined by a laser Doppler blood perfusion analysis in hind limb. However, this therapeutic regimen for ischemic limb using ADRCs did not affect remote melanoma growth nor the density of its feeder artery, angiogenesis, and lymphatic vessels compared with the PBS group. In addition, no distant metastases were detected in any of the mice regardless of the group. In conclusion, local implantation of ADRCs promotes angiogenesis in response to tissue ischemia in the hindlimb without promoting remote tumor growth and related angio/lymphangiogenesis. Therapeutic angiogenesis to the ischemic hindlimb using ADRCs seems to be safe regarding remote tumor growth.NEW & NOTEWORTHY In this study, we demonstrated that local injection of ADRCs can promote angiogenesis in response to tissue ischemia without promoting remote tumor growth in a mouse model. Our findings indicate that therapeutic angiogenesis to the ischemic hindlimb using ADRCs seems to be safe regarding remote tumor growth.