Krembil Centre for Stem Cell Biology, Robarts Research Institute, Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada.
Stem Cells. 2012 Oct;30(10):2248-60. doi: 10.1002/stem.1206.
Umbilical cord blood (UCB) represents a readily available source of hematopoietic and endothelial precursors at early ontogeny. Understanding the proangiogenic functions of these somatic progenitor subtypes after transplantation is integral to the development of improved cell-based therapies to treat ischemic diseases. We used fluorescence-activated cell sorting to purify a rare (<0.5%) population of UCB cells with high aldehyde dehydrogenase (ALDH(hi) ) activity, a conserved stem/progenitor cell function. ALDH(hi) cells were depleted of mature monocytes and T- and B-lymphocytes and were enriched for early myeloid (CD33) and stem cell-associated (CD34, CD133, and CD117) phenotypes. Although these cells were primarily hematopoietic in origin, UCB ALDH(hi) cells demonstrated a proangiogenic transcription profile and were highly enriched for both multipotent myeloid and endothelial colony-forming cells in vitro. Coculture of ALDH(hi) cells in hanging transwells promoted the survival of human umbilical vein endothelial cells (HUVEC) under growth factor-free and serum-free conditions. On growth factor depleted matrigel, ALDH(hi) cells significantly increased tube-like cord formation by HUVEC. After induction of acute unilateral hind limb ischemia by femoral artery ligation, transplantation of ALDH(hi) cells significantly enhanced the recovery of perfusion in ischemic limbs. Despite transient engraftment in the ischemic hind limb, early recruitment of ALDH(hi) cells into ischemic muscle tissue correlated with increased murine von Willebrand factor blood vessel and CD31+ capillary densities. Thus, UCB ALDH(hi) cells represent a readily available population of proangiogenic progenitors that promote vascular regeneration. This work provides preclinical justification for the development of therapeutic strategies to treat ischemic diseases using UCB-derived ALDH(hi) mixed progenitor cells.
脐带血（UCB）代表了在早期胚胎发生中造血和内皮前体细胞的易得来源。了解这些体干细胞亚型在移植后的促血管生成功能对于开发改善的基于细胞的治疗缺血性疾病的疗法至关重要。我们使用荧光激活细胞分选技术纯化了一种罕见的（<0.5％）具有高醛脱氢酶（ALDH（hi））活性的 UCB 细胞，这是一种保守的干细胞/祖细胞功能。ALDH（hi）细胞耗尽了成熟的单核细胞、T 细胞和 B 细胞，并富含早期髓样细胞（CD33）和干细胞相关（CD34、CD133 和 CD117）表型。尽管这些细胞主要来源于造血系统，但 UCB ALDH（hi）细胞表现出促血管生成的转录谱，并且在体外高度富集多能髓样细胞和内皮细胞集落形成细胞。在无生长因子和无血清条件下，在悬挂式 Transwell 中共培养 ALDH（hi）细胞可促进人脐静脉内皮细胞（HUVEC）的存活。在生长因子耗尽的基质胶上，ALDH（hi）细胞可显著增加 HUVEC 的管状cord 形成。通过股动脉结扎诱导急性单侧后肢缺血后，ALDH（hi）细胞移植可显著增强缺血肢体的灌注恢复。尽管在缺血后肢中有短暂的植入，但 ALDH（hi）细胞早期招募到缺血肌肉组织与增加的小鼠血管性血友病因子血管和 CD31+毛细血管密度相关。因此，UCB ALDH（hi）细胞代表了一种易于获得的促血管生成祖细胞群体，可促进血管再生。这项工作为使用 UCB 衍生的 ALDH（hi）混合祖细胞治疗缺血性疾病的治疗策略的发展提供了临床前依据。
