Widespread Non-Hematopoietic Tissue Distribution by Transplanted Human Progenitor Cells with High Aldehyde Dehydrogenase Activity

¹ Department of Internal Medicine, Division of Oncology, Hematopoietic Development and Malignancy Group, Washington University School of Medicine, St. Louis, MO, USA
² Department of Pathology and Laboratory Medicine, St Louis University School of Medicine, Cardinal Glennon Hospital Cord Blood Banking Facility, St Louis, MO, USA

^* To whom correspondence should be addressed. E-mail: dhess{at}robarts.ca.

	Abstract

Transplanted adult progenitor cells distribute to peripheral organs and can promote endogenous cellular repair in damaged tissues. However, development of cell-based regenerative therapies has been hindered by the lack of pre-clinical models to efficiently assess multiple organ distribution and difficulty defining human cells with regenerative function. After transplantation into beta-glucuronidase (GUSB)-deficient NOD/SCID/MPSVII mice, we characterized the distribution of lineage depleted human umbilical cord blood-derived cells purified by selection using high aldehyde dehydrogenase activity (ALDH) with CD133 co-expression. ALDH^hi or ALDH^hiCD133⁺ cells produced robust hematopoietic reconstitution, and variable levels of tissue distribution in multiple organs. GUSB⁺ donor cells that co-expressed human (HLA-A,B,C) and hematopoietic (CD45⁺) cell surface markers were the primary cell phenotype found adjacent to the vascular beds of several tissues, including islet and ductal regions of mouse pancreata. In contrast, variable phenotypes were detected in the chimeric liver, with HLA⁺/CD45⁺ cells demonstrating robust GUSB expression adjacent to blood vessels, and CD45^-/HLA^- cells with diluted GUSB expression predominant in the liver parenchyma. However, true non-hematopoietic human (HLA⁺/CD45^-) cells were rarely detected in other peripheral tissues, suggesting that these GUSB⁺/HLA^-/CD45^- cells in the liver were a result of downregulated human surface marker expression in vivo, not widespread seeding of non-hematopoietic cells. However, relying solely on continued expression of cell surface markers, as employed in traditional xenotransplantation models, may underestimate true tissue distribution. ALDH-expressing progenitor cells demonstrated widespread and tissue-specific distribution of variable cellular phenotypes, indicating that these adult progenitor cells should be explored in transplantation models of tissue damage.