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 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 hind limb ischemia (HLI) and simultaneous remote tumor implantation model. C57BL/6J background wild-type mice were injected with murine B16F10 melanoma cells on their back, one day before ischemic surgery. These mice were subjected to surgical unilateral hindlimb ischemia, followed by ADRCs 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 to the PBS group. In addition, no distant metastases were detected in any of the mice regardless the group. In conclusion, local implantation of ADRCs promotes angiogenesis in response to tissue ischemia in the hind limb without promoting remote tumor growth and related angio/lymphangiogenesis. Therapeutic angiogenesis to the ischemic hind limb using ADRCs seems to be safe regarding remote tumor growth.

中文翻译：

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肌肉注射脂肪源性再生细胞对肿瘤生长没有影响：细胞疗法治疗性血管生成的安全性评估


利用自体干/祖细胞进行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，利用自体脂肪源性再生细胞（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，使用 ADRC 进行血管生成治疗是否会促进与体内肿瘤相关的不利血管生成，仍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解决了这个临床问题。在缺血手术前一天，C57BL/6J 背景野生型小鼠的背部注射了鼠 B16F10 黑色素瘤细胞。对这些小鼠进行单侧后肢缺血手术，第二天将 ADRC 植入后肢缺血肌肉或将 PBS 注射到后肢缺血肌肉中。通过后肢激光多普勒血流灌注分析，肌内植入 ADRC 增强了组织毛细血管密度和血流。然而，与 PBS 组相比，这种使用 ADRC 治疗缺血肢体的方案并不影响远端黑色素瘤的生长，也不影响其供给动脉、血管生成和淋巴管的密度。此外，无论哪组小鼠，均未检测到远处转移。总之，局部植入 ADRC 可促进后肢组织缺血时的血管生成，而不会促进远端肿瘤生长和相关的血管/淋巴管生成。使用 ADRC 对缺血后肢进行治疗性血管生成对于远处肿瘤生长似乎是安全的。