In vivo genetic selection of renal proximal tubules

Patrice K. Held; Muhsen Al-Dhalimy; Holger Willenbring; Yassmine Akkari; Shuguang Jiang; Yumi Torimaru; Susan Olson; William H. Fleming; Milton Finegold; Markus Grompe

doi:10.1016/j.ymthe.2005.09.004

In vivo genetic selection of renal proximal tubules

Patrice K. Held, Muhsen Al-Dhalimy, Holger Willenbring, Yassmine Akkari, Shuguang Jiang, Yumi Torimaru, Susan Olson, William H. Fleming, Milton Finegold, Markus Grompe

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

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.

Original language	English (US)
Pages (from-to)	49-58
Number of pages	10
Journal	Molecular Therapy
Volume	13
Issue number	1
DOIs	https://doi.org/10.1016/j.ymthe.2005.09.004
State	Published - Jan 2006

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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10.1016/j.ymthe.2005.09.004

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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.",

author = "Held, {Patrice K.} and Muhsen Al-Dhalimy and Holger Willenbring and Yassmine Akkari and Shuguang Jiang and Yumi Torimaru and Susan Olson and Fleming, {William H.} and Milton Finegold and Markus Grompe",

note = "Funding Information: We thank Angela Major for her help with histological analysis and Henry Senephansiri and Michael Gibson for help with amino acid analysis. This work was supported by a National Institutes of Health grant (NIDDK DK-51592) to M.G. and (HL-69133) to W.H.F.",

year = "2006",

month = jan,

doi = "10.1016/j.ymthe.2005.09.004",

language = "English (US)",

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T1 - In vivo genetic selection of renal proximal tubules

AU - Held, Patrice K.

AU - Al-Dhalimy, Muhsen

AU - Willenbring, Holger

AU - Akkari, Yassmine

AU - Jiang, Shuguang

AU - Torimaru, Yumi

AU - Olson, Susan

AU - Fleming, William H.

AU - Finegold, Milton

AU - Grompe, Markus

N1 - Funding Information: We thank Angela Major for her help with histological analysis and Henry Senephansiri and Michael Gibson for help with amino acid analysis. This work was supported by a National Institutes of Health grant (NIDDK DK-51592) to M.G. and (HL-69133) to W.H.F.

PY - 2006/1

Y1 - 2006/1

N2 - 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.

AB - 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.

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In vivo genetic selection of renal proximal tubules

Abstract

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