In vivo genetic selection of renal proximal tubules.
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.
Held
Patrice K
PK
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
Al-Dhalimy
Muhsen
M
Willenbring
Holger
H
Akkari
Yassmine
Y
Jiang
Shuguang
S
Torimaru
Yumi
Y
Olson
Susan
S
Fleming
William H
WH
Finegold
Milton
M
Grompe
Markus
M
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
D014443:Tyrosine; D050560:Homogentisate 1,2-Dioxygenase; D006867:Hydrolases; C020156:fumarylacetoacetase; D006713:Homogentisic Acid