Abstract
In congenital mitochondrial DNA (mtDNA) disorders, a mixture of normal and mutated mtDNA (termed heteroplasmy) exists at varying levels in different tissues, which determines the severity and phenotypic expression of disease. Pearson marrow pancreas syndrome (PS) is a congenital bone marrow failure disorder caused by heteroplasmic deletions in mtDNA. The cause of the hematopoietic failure in PS is unknown, and adequate cellular and animal models are lacking. Induced pluripotent stem (iPS) cells are particularly amenable for studying mtDNA disorders, as cytoplasmic genetic material is retained during direct reprogramming. Here, we derive and characterize iPS cells from a patient with PS. Taking advantage of the tendency for heteroplasmy to change with cell passage, we isolated isogenic PS-iPS cells without detectable levels of deleted mtDNA. We found that PS-iPS cells carrying a high burden of deleted mtDNA displayed differences in growth, mitochondrial function, and hematopoietic phenotype when differentiated in vitro, compared to isogenic iPS cells without deleted mtDNA. Our results demonstrate that reprogramming somatic cells from patients with mtDNA disorders can yield pluripotent stem cells with varying burdens of heteroplasmy that might be useful in the study and treatment of mitochondrial diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 1287-1297 |
| Number of pages | 11 |
| Journal | Stem Cells |
| Volume | 31 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2013 |
| Externally published | Yes |
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Keywords
- Hematopoiesis
- Heteroplasmy
- Human genetics
- Induced pluripotent stem cells
- Mitochondrial DNA
- Pearson's marrow pancreas syndrome
ASJC Scopus subject areas
- Cell Biology
- Developmental Biology
- Molecular Medicine
Cite this
Induced pluripotent stem cells with a mitochondrial dna deletion. / Cherry, Anne B C; Gagne, Katelyn E.; McLoughlin, Erin M.; Baccei, Anna; Gorman, Bryan; Hartung, Odelya; Miller, Justine D.; Zhang, Jin; Zon, Rebecca L.; Ince, Tan; Neufeld, Ellis J.; Lerou, Paul H.; Fleming, Mark D.; Daley, George Q.; Agarwal, Suneet.
In: Stem Cells, Vol. 31, No. 7, 01.07.2013, p. 1287-1297.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Induced pluripotent stem cells with a mitochondrial dna deletion
AU - Cherry, Anne B C
AU - Gagne, Katelyn E.
AU - McLoughlin, Erin M.
AU - Baccei, Anna
AU - Gorman, Bryan
AU - Hartung, Odelya
AU - Miller, Justine D.
AU - Zhang, Jin
AU - Zon, Rebecca L.
AU - Ince, Tan
AU - Neufeld, Ellis J.
AU - Lerou, Paul H.
AU - Fleming, Mark D.
AU - Daley, George Q.
AU - Agarwal, Suneet
PY - 2013/7/1
Y1 - 2013/7/1
N2 - In congenital mitochondrial DNA (mtDNA) disorders, a mixture of normal and mutated mtDNA (termed heteroplasmy) exists at varying levels in different tissues, which determines the severity and phenotypic expression of disease. Pearson marrow pancreas syndrome (PS) is a congenital bone marrow failure disorder caused by heteroplasmic deletions in mtDNA. The cause of the hematopoietic failure in PS is unknown, and adequate cellular and animal models are lacking. Induced pluripotent stem (iPS) cells are particularly amenable for studying mtDNA disorders, as cytoplasmic genetic material is retained during direct reprogramming. Here, we derive and characterize iPS cells from a patient with PS. Taking advantage of the tendency for heteroplasmy to change with cell passage, we isolated isogenic PS-iPS cells without detectable levels of deleted mtDNA. We found that PS-iPS cells carrying a high burden of deleted mtDNA displayed differences in growth, mitochondrial function, and hematopoietic phenotype when differentiated in vitro, compared to isogenic iPS cells without deleted mtDNA. Our results demonstrate that reprogramming somatic cells from patients with mtDNA disorders can yield pluripotent stem cells with varying burdens of heteroplasmy that might be useful in the study and treatment of mitochondrial diseases.
AB - In congenital mitochondrial DNA (mtDNA) disorders, a mixture of normal and mutated mtDNA (termed heteroplasmy) exists at varying levels in different tissues, which determines the severity and phenotypic expression of disease. Pearson marrow pancreas syndrome (PS) is a congenital bone marrow failure disorder caused by heteroplasmic deletions in mtDNA. The cause of the hematopoietic failure in PS is unknown, and adequate cellular and animal models are lacking. Induced pluripotent stem (iPS) cells are particularly amenable for studying mtDNA disorders, as cytoplasmic genetic material is retained during direct reprogramming. Here, we derive and characterize iPS cells from a patient with PS. Taking advantage of the tendency for heteroplasmy to change with cell passage, we isolated isogenic PS-iPS cells without detectable levels of deleted mtDNA. We found that PS-iPS cells carrying a high burden of deleted mtDNA displayed differences in growth, mitochondrial function, and hematopoietic phenotype when differentiated in vitro, compared to isogenic iPS cells without deleted mtDNA. Our results demonstrate that reprogramming somatic cells from patients with mtDNA disorders can yield pluripotent stem cells with varying burdens of heteroplasmy that might be useful in the study and treatment of mitochondrial diseases.
KW - Hematopoiesis
KW - Heteroplasmy
KW - Human genetics
KW - Induced pluripotent stem cells
KW - Mitochondrial DNA
KW - Pearson's marrow pancreas syndrome
UR - http://www.scopus.com/inward/record.url?scp=84879907981&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879907981&partnerID=8YFLogxK
U2 - 10.1002/stem.1354
DO - 10.1002/stem.1354
M3 - Article
C2 - 23400930
AN - SCOPUS:84879907981
VL - 31
SP - 1287
EP - 1297
JO - Stem Cells
JF - Stem Cells
SN - 1066-5099
IS - 7
ER -