Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver

Harmeet M Malhi, Pallavi Annamaneni, Sanjeev Slehria, Brigid Joseph, Kuldeep K. Bhargava, Christopher J. Palestro, Phyllis M. Novikoff, Sanjeev Gupta

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)112-121
Number of pages10
JournalHepatology
Volume36
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

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Cyclophosphamide
Endothelium
Liver
Dipeptidyl Peptidase 4
Hepatocytes
Cell Transplantation
Inbred F344 Rats
Bile Canaliculi
Kupffer Cells
Hepatectomy
Cell- and Tissue-Based Therapy
Cell Size
Electron Microscopy
Cell Count
Transplantation
Cell Proliferation
Wounds and Injuries

ASJC Scopus subject areas

  • Hepatology

Cite this

Malhi, H. M., Annamaneni, P., Slehria, S., Joseph, B., Bhargava, K. K., Palestro, C. J., ... Gupta, S. (2002). Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver. Hepatology, 36(1), 112-121. https://doi.org/10.1053/jhep.2002.33896

Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver. / Malhi, Harmeet M; Annamaneni, Pallavi; Slehria, Sanjeev; Joseph, Brigid; Bhargava, Kuldeep K.; Palestro, Christopher J.; Novikoff, Phyllis M.; Gupta, Sanjeev.

In: Hepatology, Vol. 36, No. 1, 2002, p. 112-121.

Research output: Contribution to journalArticle

Malhi, HM, Annamaneni, P, Slehria, S, Joseph, B, Bhargava, KK, Palestro, CJ, Novikoff, PM & Gupta, S 2002, 'Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver', Hepatology, vol. 36, no. 1, pp. 112-121. https://doi.org/10.1053/jhep.2002.33896
Malhi, Harmeet M ; Annamaneni, Pallavi ; Slehria, Sanjeev ; Joseph, Brigid ; Bhargava, Kuldeep K. ; Palestro, Christopher J. ; Novikoff, Phyllis M. ; Gupta, Sanjeev. / Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver. In: Hepatology. 2002 ; Vol. 36, No. 1. pp. 112-121.
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