Derderian S Christopher, Moradi P Wais, MacKenzie Tippi C
Eli and Edythe Broad Center of Regeneration Medicine, The Department of Surgery, University of California, San Francisco, CA, USA.
Eli and Edythe Broad Center of Regeneration Medicine, The Department of Surgery, University of California, San Francisco, CA, USA.
J Pediatr Surg. 2015 Sep;50(9):1517-20. doi: 10.1016/j.jpedsurg.2014.12.021. Epub 2014 Dec 31.
The success of in utero hematopoietic cell transplantation (IUHCTx) hinges on successful conditioning strategies of the host to overcome barriers to engraftment. The "space" barrier is a reflection of a finite number of hematopoietic stem cell (HSC) niches within the host. Independent of the number of donor HSCs transplanted, engraftment is frequently low. By conditioning fetal mice using a monoclonal antibody against the c-kit receptor (ACK2) found on HSCs, we can effectively increase space for donor HSC engraftment. We questioned whether simple placental injection of ACK2 early in gestation could effectively deplete host HSCs within the fetal liver and neonatal bone marrow.
In this set of experiments, we injected mice with ACK2 (5 μg/fetus) or PBS at E11.5-12.5 and harvested the fetal liver at 2 and 4 days and the neonatal bone marrow at 7 days following injection. Survival and total number of HSCs within the fetal liver or bone marrow were quantified and compared.
Survival between the treated and control group was similar (73% and 71%, respectively). The total number of HSCs within the fetal liver was not significantly lower following ACK2 treatment compared to PBS injected fetuses at 2 days but was by 4 days. Additionally, ACK2 resulted in a significant reduction in the number of HSCs within neonatal mice 7 days after treatment.
Survival following placental ACK2 injection is comparable to control animals and provides a simple non-invasive strategy to deliver ACK2 into the fetal circulation which successfully depletes the host HSCs.
宫内造血细胞移植（IUHCTx）的成功取决于对宿主成功的预处理策略，以克服植入障碍。“空间”障碍反映了宿主内有限数量的造血干细胞（HSC）龛位。与移植的供体造血干细胞数量无关，植入率通常较低。通过使用针对造血干细胞上发现的c-kit受体的单克隆抗体（ACK2）对胎鼠进行预处理，我们可以有效地增加供体造血干细胞植入的空间。我们质疑在妊娠早期简单地经胎盘注射ACK2是否能有效耗尽胎肝和新生骨髓中的宿主造血干细胞。
在这组实验中，我们在胚胎第11.5 - 12.5天给小鼠注射ACK2（5μg/胎儿）或PBS，并在注射后2天和4天收获胎肝，在7天收获新生骨髓。对胎肝或骨髓中造血干细胞的存活情况和总数进行定量并比较。
治疗组和对照组的存活率相似（分别为73%和71%）。与注射PBS的胎儿相比，在注射后2天，ACK2处理后胎肝内造血干细胞的总数没有显著降低，但在4天时降低了。此外，ACK2导致治疗后7天新生小鼠体内造血干细胞数量显著减少。
经胎盘注射ACK2后的存活率与对照动物相当，并提供了一种简单的非侵入性策略，将ACK2输送到胎儿循环中，成功耗尽宿主造血干细胞。
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