Myelomonocytic cells are sufficient for therapeutic cell fusion in liver

Abstract

Liver repopulation with bone marrow-derived hepatocytes (BMHs) can cure the genetic liver disease fumarylacetoacetate hydrolase (Fah) deficiency. BMHs emerge from fusion between donor bone marrow-derived cells and host hepatocytes. To use such in vivo cell fusion efficiently for therapy requires knowing the nature of the hematopoietic cells that fuse with hepatocytes. Here we show that the transplantation into Fah(-/-) mice of hematopoietic stem cells (HSCs) from lymphocyte-deficient Rag1(-/-) mice, lineage-committed granulocyte-macrophage progenitors (GMPs) or bone marrow-derived macrophages (BMMs) results in the robust production of BMHs. These results provide direct evidence that committed myelomonocytic cells such as macrophages can produce functional epithelial cells by in vivo fusion. Because stable bone marrow engraftment or HSCs are not required for this process, macrophages or their highly proliferative progenitors provide potential for targeted and well-tolerated cell therapy aimed at organ regeneration.

Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells

“…This observation may explain recent reports of heterogeneous cell-cell fusion between macrophages and somatic cells or cancer cells. (11,32) Hepatocyte-macrophage cell-cell fusion was also observed in Fah-deficient mice, and fusion was crucial to overcome a lethal defect in liver function due to Fah-deficiency. (11) Meanwhile, tumor-macrophage fusion is thought to promote chemoresistance or metastatic potential (32) and alter tumor cell properties.…”

“…(11,32) Hepatocyte-macrophage cell-cell fusion was also observed in Fah-deficient mice, and fusion was crucial to overcome a lethal defect in liver function due to Fah-deficiency. (11) Meanwhile, tumor-macrophage fusion is thought to promote chemoresistance or metastatic potential (32) and alter tumor cell properties. Further studies are needed to explore mechanisms underlying heterophilic cell-cell fusion via macrophages.…”

“…(10) Macrophage cell-cell fusion reportedly functions in tissue repair. (11) Osteoclasts are also known to function in tissue destruction in conditions such as metastatic bone tumors, (12) whereas FBGCs have been demonstrated to induce matrix degradation. (13) Therefore, although the functions of osteoclasts and FBGCs differ, they express common molecules, such as DC-STAMP, that function in cell-cell fusion.…”

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

“…32 For the analysis of myeloid progenitors, bone marrow cells were labeled with a PE-conjugated lineage mixture (CD3e, CD4, CD8a, B220, Ter119, Gr1, CD19, and immunoglobulin M) and anti-interleukin-7 receptor-alpha (IL-7R-␣)-PE, anti-Sca-1-PE, anti-c-Kit-APC, anti-CD34-fluorescein isothiocyanate (FITC), and anti-Fc-␥RII/III-PE-Cy7 antibodies. Common myeloid progenitors (CMPs) were defined as IL-7R-␣ Ϫ Lin Ϫ Sca-1 Ϫ cKit ϩ CD34 ϩ Fc-␥RII/III low , and granulocyte-macrophage progenitors (GMPs) were defined as IL-7R-␣ Ϫ Lin Ϫ Sca-1 Ϫ c-Kit ϩ CD34 ϩ Fc-␥RII/III high .…”

Cellules souches hépatiques : tout un programme !

“…Chez le rongeur, il a été démontré que les hépatocytes dérivés de la moelle provenaient en réalité d'un événement de fusion entre une cellule myélomonocy-taire issue de la moelle donneuse [5][6][7] et un hépatocyte résident. Cependant, d'autres résultats sont venus récemment contredire cette observation: il serait en effet possible d'obtenir des cellules hépatiques à partir de cellules médul-laires en l'absence de fusion in vivo chez la souris [8] ou dans le modèle du foie foetal de mouton [4], voire in vitro lorsque des cellules souches hématopoïé-tiques sont mises en présence de sérum d'animaux au foie lésé [9].…”