title: In vivo genetic selection of renal proximal tubules.
abstract: Repopulation by transplanted cells can result in effective therapy for several regenerative organs including blood, liver, and skin. In contrast, cell therapies for renal diseases are not currently available. Here we developed an animal model in which cells genetically resistant to a toxic intermediate of tyrosine metabolism, homogentisic acid (HGA), were able to repopulate the damaged proximal tubule epithelium of mice with fumarylacetoacetate hydrolase (Fah) deficiency. HGA resistance was achieved by two independent mechanisms. First, Fah+ transplanted bone marrow cells produced significant replacement of damaged proximal tubular epithelium (up to 50%). The majority of bone marrow-derived epithelial cells were generated by cell fusion, not transdifferentiation. In addition to regeneration by fusion-derived epithelial cells, proximal tubular repopulation was also observed by host epithelial cells, which had lost the homogentisic acid dioxygenase gene. These data demonstrate that extensive regeneration of the renal proximal tubule compartment can be achieved through genetic selection of functional cells.
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Patrice K
authors.initials: PK
authors.lastname: Held
authors.forename: Muhsen
authors.initials: M
authors.lastname: Al-Dhalimy
authors.forename: Holger
authors.initials: H
authors.lastname: Willenbring
authors.forename: Yassmine
authors.initials: Y
authors.lastname: Akkari
authors.forename: Shuguang
authors.initials: S
authors.lastname: Jiang
authors.forename: Yumi
authors.initials: Y
authors.lastname: Torimaru
authors.forename: Susan
authors.initials: S
authors.lastname: Olson
authors.forename: William H
authors.initials: WH
authors.lastname: Fleming
authors.forename: Milton
authors.initials: M
authors.lastname: Finegold
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
mesh_terms: D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002459:Cell Fusion; D002908:Chronic Disease; D004195:Disease Models, Animal; D050560:Homogentisate 1,2-Dioxygenase / Q000235:genetics; D006713:Homogentisic Acid / Q000378:metabolism*; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D012038:Regeneration; D014443:Tyrosine / Q000378:metabolism; D019459:Urothelium / Q000201:enzymology / Q000473:pathology
chemical_list: D014443:Tyrosine; D050560:Homogentisate 1,2-Dioxygenase; D006867:Hydrolases; C020156:fumarylacetoacetase; D006713:Homogentisic Acid