In utero transplantation: hepatic potential of human CD34⁺CD45⁺ progenitors

Comment on Almeida-Porada et al, page 2582

In utero–injected, long-term repopulating human hematopoietic stem and progenitor cells are capable of hepatic differentiation in the liver of preimmune sheep.

Liver-specific injuries applied in rodent models have demonstrated that hematopoietic progenitor subpopulations have the potential to migrate to and repopulate the injured liver, as well as to acquire hepatic phenotype and function. While most studies suggest fusion as the major mechanism mediating this phenotype, preliminary studies provide evidence of hepatic differentiation by bone marrow cells, which does not require cell fusion.^1,2  Does the hepatic phenotype and, more importantly, function require liver injury/stress as a crucial trigger for this fate-converting pathway? Recently, immature human CD34⁺CXCR4⁺CD45^– progenitors, with migration potential to stromal-derived factor-1 (SDF-1, also termed CXCL12), were found to already express liver-specific genes while still residing in the bone marrow (BM).³  These data evoke new questions. Does the injured/irradiated liver induce the expression of liver-specific genes or is it an intrinsic attribute of CD45^– BM-committed progenitors? Does the BM serve as a reservoir for CXCR4⁺ progenitors expressing tissue-specific genes, ready for stress-induced recruitment to the injured organ? Can these cells migrate to the liver in response to SDF-1 signaling and develop into hepatocytes as shown before for immature hepatic oval cells,⁴  human CD34 progenitors,⁵  and murine BM stem cells,²  even without liver injury/damage or total body irradiation?FIG1 

In this issue of Blood, Almeida-Porada and colleagues provide an important contribution to our understanding of the developmental program of human bone marrow CD34⁺CD38^– CD45⁺ progenitor cells. Using the highly proliferative and permissive microenvironment of the preimmunefetalsheep,theauthorsaskedwhether undifferentiated human progenitors with long-term hematopoietic repopulation potential can also give rise to hepatocytes without inducing liver injury. Enriched human CD34⁺ cells first repopulatedtheBMofprimaryfetalsheeprecipients with human CD45⁺ cells that were harvested a few months later, enriched, and used for serial-secondary transplantations. The livers of primary and secondary recipients were tested for the presence of human and sheep hepatocytes. High frequencies (of up to 17%) of human hepatocytes with no evidence for cell fusion were readily detected. BM-derivedhuman CD34⁺Lin^– cells were found to have higher hepatic potential compared with circulating cord blood (CB) or mobilized peripheral blood CD34⁺Lin^– cells. These findings suggest that the capacity of liver differentiation is an intrinsic feature of human CD34⁺ BM progenitors and that exposure to injured/irradiated liver microenvironment is not a prerequisite for hepatic commitment, provided that this organ is actively developing. Furthermore, primitive BM-derived CD34⁺CD38^–Lin^– cells, previously shown to have CXCR4-dependent stem cell repopulation potenital, when transplanted in nonobese diabetic/severe combined immune deficient (NOD/SCID) mice (SCID repopulating cell, SRC) are shown in the present study to also have the highest hepatic potential. Interestingly, another primitive subpopulation of undifferentiated hematopoieticcells,CD34^–CD38^– Lin^– cells with preimmune sheep repopulation potential, also gave rise to human hepatocytes in secondary recipients. A novel and significant finding reported in this study is that hematopoietic human cells expressing the pan-leukocyte marker CD45 can give rise to both populations: CD45⁺ BM hematopoietic cells and CD45^– hepatocytes with no evidence for cell fusion. This most interesting finding is of importance in characterizing the mechanism of hepatic development from BM progenitors. Future studies using gene marking or single stem cell–based transplantations will reveal whether these distinct populations are derived from different CD34⁺/CD38^– and CD34^–/CD38^– progenitors or if a common hematopoietic/hepatic CD45⁺ precursor within the BM is a potent candidate capable of both hematopoietic and hepatic regeneration. Additional investigations will reveal whether these cells, which migrate to the developing liver, are responding to SDF-1 signals, also in physiologic conditions, without liver injury.

Finally, the results of this study suggest the possibility of cellular therapy for liver metabolic disorders, which can be diagnosed during pregnancy, by in utero bone marrow transplantation. ▪