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Differences in mobilization of rare hematopoietic stem cells from human liver grafts of non-heart beating and heart beating donors

Hall, S.R.R., Pan, Q., Pedroza-Gonzalez, A., Bruin, R.W.F. de, Kwekkeboom, J., Metselaar, H.J., Laan, L.J.W. van der, Tilanus, H.W., Wagemaker, G., Jonge, J. de

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Background Profound physiological changes following organ donation results in liver injury.  However, these same physiological changes may induce trafficking of hematopoietic stem/progenitor cells (HSPCs) as a restitutive response to limit tissue injury. The aim of this study was to determine if there are differences in the mobilization of HSPCs from liver grafts procured from heart beating (HB) versus non-heart beating (NHB) donors at time of transplantation.

 

Methods During liver transplantation, graft preservation solutions (perfusates) of nine HB and seven NHB donor livers were collected. Liver perfusate mononuclear cells (MNCs), isolated using ficoll, were stained with a cocktail of mAbs specific for human lineage markers (Lin)-FITC, CD34-PE, CD90-APC, CD38-APC-Cy7 and CD45RA-PB to examine HSPC populations by polychromatic flow cytometry. Additionally, in vitro colony-forming unit assays were performed to assess the lineage-restriction of the HSPCs.

 

Results Polychromatic flow cytometric analysis revealed a difference in the mobilization of liver-perfusate derived live Lin-CD34+CD38- stem/progenitor cells from HB (0.36% ± 0.48, mean±SD) versus NHB donors (0.035% ± 0.038). Within the total CD34+ subset, we found 0.14% ± 0.06 CD34+CD11b- and 0.09% ± 0.07 CD34+HLA-DR- single positive cells, generally considered as undifferentiated HSCs. The colony forming assays revealed that 325 ± 115 erythroid colonies (CFU-e), 103 ± 67 erythroid burst-forming units (BFU-e) and 36 ± 28 granulocyte progenitors units (CFU-c) were present per million mononuclear cells. This frequency of colony forming cells is almost 10-fold higher than those found in peripheral blood and 10-fold lower than in bone marrow. After liver transplantation, donor HSC continue to migrate from the graft in the first months as was shown by the approx. 2-8% of circulating CD34+ cells being of donor origin.

 

Discussion We found an enhanced mobilization of HSPCs from livers procured from HB donors compared to NHB donors. Moreover, liver-derived cells with a distinct hematopoietic phenotype give rise to substantial numbers of colony-forming units in vitro, confirming that HSPCs are present in adult human liver and mobilize during liver perfusion. Mobilized liver HSPCs may contribute to hematopoietic chimerism and allohyporesponsiveness after liver transplantation.