Human cord blood CD34 ⁺ cells develop into hepatocytes in the livers of NOD/SCID/γ _c ^null mice through cell fusion

Abstract

Several studies have shown that hepatocytes can be generated from hematopoietic stem cells, but this event is believed to be rare and to require hepatic damage. To investigate this phenomenon in human cells, we used a NOD/SCID/gamma(c)null (NOG) mouse model that can achieve a tremendously high level of chimerism when transplanted with human hematopoietic cells. Even without hepatotoxic treatment other than irradiation, human albumin and alpha-1-antitrypsin-positive cells were invariably detected in the livers of NOG mice after i.v. transplantation of human cord blood CD34+ cells. Human albumin was detected in the murine sera, indicating functional maturation of the human hepatocytes. Flow cytometric analysis of recipient liver cells in single-cell suspension demonstrated that human albumin-positive cells were also positive for both murine and human MHC and were negative for human CD45. PCR analysis of recipient livers revealed the expression of a wide variety of human hepatocyte- or cholangiocyte-specific mRNAs. These results show that human CD34+ cells fuse with hepatocytes of NOG mice without liver injury, lose their hematopoietic phenotype, and begin hepatocyte-specific gene transcription. These phenomena were not observed when CD34- cells were transplanted. Thus, our model revealed a previously unidentified pathway of human hematopoietic stem/progenitor cell differentiation.

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…Rat MSCs can also differentiate into hepatocytes in vitro and these cells continue to function after transplantation into DPPIV-negative rats, again predominantly in the periportal area [108]. As expected, a number of transplantation studies report fusion between donor and recipient cells, including human cord blood with sublethally irradiated mouse hepatocytes [109] and mouse bone marrow with mouse hepatocytes after CCl 4 injury [110]: the benefits of cell fusion in the context of hepatocyte injury are not immediately obvious.…”

Cellules souches embryonnaires humaines et iPS

“…Dans un certain nombre de cas, ce phénomène correspond à une fusion de cellules hématopoïétiques avec les hépatocytes endogènes [31,32]. Les cellules souches mésenchymateuses (CSM) sont d'un intérêt potentiel certain, mais les données actuelles suggèrent qu'elles jouent un rôle essentiellement de support trophique dans les foies lésés en inhibant la mort des hépatocytes et en stimulant leur prolifération [33][34][35][36].…”

Hybrid cells differentiate to hepatic lineage cells and repair oxidative damage

“…At the end of each time point (12,24,36,48 and 60 h), the supernatant was collected to measure the secretion of ALB and the levels of the enzymes: glutathione peroxidase (GSH-Px), super oxide dismutase (SOD) and lactate dehydrogenase (LDH). LDH activity in the supernatant was measured via spectrophotometry.…”

“…Therefore, in our study, hybrid cells derived from hepatic cells have a particular function to inhibit the apoptosis of hepatic cells. It was reported that fusion occurs, under selective pressure, such as under conditions of damage [47][48][49][50]. Fusion occurred spontaneously in vivo after transplantation and in vitro after co-culturing [26,50].…”

“…Fusion occurred under selective pressure such as under conditions of damage [47,[49][50]. However, only by irradiation did human cord blood CD34+ cells still develop into hepatocytes in the liver [48]. It is notable that CD34 is a 110-kDa transmembrane glycoprotein.…”