Malhi Harmeet, Annamaneni Pallavi, Slehria Sanjeev, Joseph Brigid, Bhargava Kuldeep K, Palestro Christopher J, Novikoff Phyllis M, Gupta Sanjeev
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Ullmann 625, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Hepatology. 2002 Jul;36(1):112-21. doi: 10.1053/jhep.2002.33896.
To determine whether disruption of the hepatic sinusoidal endothelium will facilitate engraftment of transplanted cells, we treated Fischer 344 (F344) rats lacking dipeptidyl peptidase IV (DPPIV) activity with cyclophosphamide (CP). Electron microscopy showed endothelial injury within 6 hours following CP, and, after 24 and 48 hours, the endothelium was disrupted in most hepatic sinusoids. CP did not affect Kupffer cell function. Similarly, CP had no obvious effects on hepatocytes. Intrasplenic transplantation of F344 rat hepatocytes followed by their localization with DPPIV histochemistry showed 3- to 5-fold increases in the number of transplanted cells in CP-treated animals. Transplanted cells integrated in the liver parenchyma more rapidly in CP-treated animals, and hybrid bile canaliculi developed even 1 day after cell transplantation, which was not observed in control animals. To demonstrate whether improved cell engraftment translated into superior liver repopulation, recipient animals were conditioned with retrorsine and two-thirds partial hepatectomy (PH), which induces transplanted cell proliferation. CP treatment of these animals before cell transplantation significantly increased the number and size of transplanted cell foci. In conclusion, disruption of the hepatic sinusoidal endothelium was associated with accelerated entry and integration of transplanted cells in the liver parenchyma. These results provide insights into hepatocyte engraftment in the liver and will help in optimizing liver-directed cell therapy.
为了确定肝血窦内皮的破坏是否会促进移植细胞的植入，我们用环磷酰胺（CP）处理缺乏二肽基肽酶IV（DPPIV）活性的Fischer 344（F344）大鼠。电子显微镜显示，CP处理后6小时内出现内皮损伤，24小时和48小时后，大多数肝血窦的内皮被破坏。CP不影响库普弗细胞功能。同样，CP对肝细胞也无明显影响。对F344大鼠肝细胞进行脾内移植，然后用DPPIV组织化学进行定位，结果显示，CP处理组动物的移植细胞数量增加了3至5倍。在CP处理的动物中，移植细胞更快地整合到肝实质中，甚至在细胞移植后1天就形成了混合胆小管，而在对照动物中未观察到这种情况。为了证明细胞植入的改善是否转化为更好的肝脏再填充，对受体动物用倒千里光碱和三分之二部分肝切除术（PH）进行预处理，这会诱导移植细胞增殖。在细胞移植前对这些动物进行CP处理，显著增加了移植细胞灶的数量和大小。总之，肝血窦内皮的破坏与移植细胞在肝实质中的加速进入和整合有关。这些结果为肝脏中肝细胞的植入提供了见解，并将有助于优化肝脏定向细胞治疗。
