Engraftment of Donor‐Derived Epithelial Cells in Multiple Organs Following Bone Marrow Transplantation into Newborn Mice

Abstract

Bone marrow-derived cells (BMDCs) can engraft as epithelial cells throughout the body, including in the lung, liver, and gastrointestinal (GI) tract following transplantation into lethally irradiated adult recipients. Except for rare disease models in which marrow-derived epithelial cells have a survival advantage over endogenous cells, the currently attained levels of epithelial engraftment of BMDCs are too low to be of therapeutic benefit. Here we tested whether the degree of bone marrow to epithelial engraftment would be higher if bone marrow transplantation (BMT) were performed on 1-day-old mice, when tissues are undergoing rapid growth and remodeling. BMT into newborn mice after multiple different regimens allowed for robust hematopoietic engraftment, as well as the development of rare donor-derived epithelial cells in the GI tract and lung but not in the liver. The highest epithelial engraftment (0.02%) was obtained in mice that received a preparative regimen of two doses of busulfan in utero. When BMDCs were transplanted into myelosuppressed newborn mice that lacked expression of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, the chloride channel that is not functional in patients with cystic fibrosis, the engrafted mice showed partial restoration of CFTR channel activity, suggesting that marrow-derived epithelial cells in the GI tract were functional. However, BMT into newborn mice, regardless of the myeloablative regimen used, did not increase the number of bone marrow-derived epithelial cells over that which occurs after BMT into lethally irradiated adult mice.

Hematopoietic Stem/Progenitor Cells Express Functional Mitochondrial Energy-Dependent Cystic Fibrosis Transmembrane Conductance Regulator

“…Meanwhile, engraftment studies have been made also in CF mice. Transplantation of wild-type cultured stromal marrow cells [57] or whole BM [58,59] into CF mice resulted in the engraftment of donorderived airway epithelial cells in small numbers only (between 0.01% and 0.025%). Interestingly, Bruscia et al [58,59] found a partial resumption of the CFTR-mediated chloride currents to wild-type levels in both gut and nose, although they could not explain this effect in face of a very low engraftment level.…”

Identification of mesenchymal stromal cells in human lung parenchyma capable of differentiating into aquaporin 5-expressing cells

“…These studies, however, have been plagued with inconsistent results and controversy as to whether adult bone marrow stromal cells really engraft and differentiate into lung phenotypes. 23,36 The present consensus seems to be that engraftment of bone marrow-derived MSCs in the lung does occur, but at the very low rates of approximately 0.01-0.1%, 36,37 and hence they are unlikely to be a practical option for cell-based therapy studies.…”

Cells of Epithelial Lineage Are Present in Blood, Engraft the Bronchial Epithelium, and Are Increased in Human Lung Transplantation

“…The implied aim is that these therapies will be deliverable to target organs and that substantial, clinically significant engraftment will occur. This aim is by no means assured, and indeed animal studies 17,18 have suggested that the inability to achieve large-scale engraftment may be the greatest barrier to successful application of cellular therapeutics. The surface expression of CXCR4 on engrafting cells provides a clue to the mechanism of pulmonary engraftment of exogenous epithelial cells.…”