Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency
Dysfunctional stem cell differentiation into placental lineages is associated with gestational diseases. Of the differentiated lineages available to trophoblast stem cells (TSC), elevated O2 and mitochondrial function are necessary to placental lineages at the maternal–placental surface and importan...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-11-01
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| Series: | Stem Cell Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1873506114000889 |
| _version_ | 1828254803678986240 |
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| author | Yufen Xie Sichang Zhou Zhongliang Jiang Jing Dai Elizabeth E. Puscheck Icksoo Lee Graham Parker Maik Hüttemann Daniel A. Rappolee |
| author_facet | Yufen Xie Sichang Zhou Zhongliang Jiang Jing Dai Elizabeth E. Puscheck Icksoo Lee Graham Parker Maik Hüttemann Daniel A. Rappolee |
| author_sort | Yufen Xie |
| collection | DOAJ |
| description | Dysfunctional stem cell differentiation into placental lineages is associated with gestational diseases. Of the differentiated lineages available to trophoblast stem cells (TSC), elevated O2 and mitochondrial function are necessary to placental lineages at the maternal–placental surface and important in the etiology of preeclampsia. TSC lineage imbalance leads to embryonic failure during uterine implantation. Stress at implantation exacerbates stem cell depletion by decreasing proliferation and increasing differentiation. In an implantation site O2 is normally ~2%. In culture, exposure to 2% O2 and fibroblast growth factor 4 (FGF4) enabled the highest mouse TSC multipotency and proliferation. In contrast, hypoxic stress (0.5% O2) initiated the most TSC differentiation after 24 h despite exposure to FGF4. However, hypoxic stress supported differentiation poorly after 4–7 days, despite FGF4 removal. At all tested O2 levels, FGF4 maintained Warburg metabolism; mitochondrial inactivity and aerobic glycolysis. However, hypoxic stress suppressed mitochondrial membrane potential and maintained low mitochondrial cytochrome c oxidase (oxidative phosphorylation/OxPhos), and high pyruvate kinase M2 (glycolysis) despite FGF4 removal. Inhibiting OxPhos inhibited optimum differentiation at 20% O2. Moreover, adding differentiation-inducing hyperosmolar stress failed to induce differentiation during hypoxia. Thus, differentiation depended on OxPhos at 20% O2; hypoxic and hyperosmolar stresses did not induce differentiation at 0.5% O2. Hypoxia-limited differentiation and mitochondrial inhibition and activation suggest that differentiation into two lineages of the labyrinthine placenta requires O2 > 0.5–2% and mitochondrial function. Stress-activated protein kinase increases an early lineage and suppresses later lineages in proportion to the deviation from optimal O2 for multipotency, thus it is the first enzyme reported to prioritize differentiation. |
| first_indexed | 2024-04-13T02:04:28Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1873-5061 1876-7753 |
| language | English |
| last_indexed | 2024-04-13T02:04:28Z |
| publishDate | 2014-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Research |
| spelling | doaj.art-f69df3839103415f8070a425161277912022-12-22T03:07:32ZengElsevierStem Cell Research1873-50611876-77532014-11-0113347849110.1016/j.scr.2014.07.007Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiencyYufen Xie0Sichang Zhou1Zhongliang Jiang2Jing Dai3Elizabeth E. Puscheck4Icksoo Lee5Graham Parker6Maik Hüttemann7Daniel A. Rappolee8CS Mott Center for Human Growth and Development, Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, MI 48201, USACS Mott Center for Human Growth and Development, Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, MI 48201, USACS Mott Center for Human Growth and Development, Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, MI 48201, USACS Mott Center for Human Growth and Development, Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, MI 48201, USACS Mott Center for Human Growth and Development, Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, MI 48201, USACollege of Medicine, Dankook University, Cheonan-si, Chungcheongnam-do 330-714, Republic of KoreaDepartment of Pediatrics and Children's Hospital of Michigan, Wayne State University School of Medicine, USACenter for Molecular Medicine and Genetics, Wayne State University School of Medicine, USACS Mott Center for Human Growth and Development, Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, MI 48201, USADysfunctional stem cell differentiation into placental lineages is associated with gestational diseases. Of the differentiated lineages available to trophoblast stem cells (TSC), elevated O2 and mitochondrial function are necessary to placental lineages at the maternal–placental surface and important in the etiology of preeclampsia. TSC lineage imbalance leads to embryonic failure during uterine implantation. Stress at implantation exacerbates stem cell depletion by decreasing proliferation and increasing differentiation. In an implantation site O2 is normally ~2%. In culture, exposure to 2% O2 and fibroblast growth factor 4 (FGF4) enabled the highest mouse TSC multipotency and proliferation. In contrast, hypoxic stress (0.5% O2) initiated the most TSC differentiation after 24 h despite exposure to FGF4. However, hypoxic stress supported differentiation poorly after 4–7 days, despite FGF4 removal. At all tested O2 levels, FGF4 maintained Warburg metabolism; mitochondrial inactivity and aerobic glycolysis. However, hypoxic stress suppressed mitochondrial membrane potential and maintained low mitochondrial cytochrome c oxidase (oxidative phosphorylation/OxPhos), and high pyruvate kinase M2 (glycolysis) despite FGF4 removal. Inhibiting OxPhos inhibited optimum differentiation at 20% O2. Moreover, adding differentiation-inducing hyperosmolar stress failed to induce differentiation during hypoxia. Thus, differentiation depended on OxPhos at 20% O2; hypoxic and hyperosmolar stresses did not induce differentiation at 0.5% O2. Hypoxia-limited differentiation and mitochondrial inhibition and activation suggest that differentiation into two lineages of the labyrinthine placenta requires O2 > 0.5–2% and mitochondrial function. Stress-activated protein kinase increases an early lineage and suppresses later lineages in proportion to the deviation from optimal O2 for multipotency, thus it is the first enzyme reported to prioritize differentiation.http://www.sciencedirect.com/science/article/pii/S1873506114000889 |
| spellingShingle | Yufen Xie Sichang Zhou Zhongliang Jiang Jing Dai Elizabeth E. Puscheck Icksoo Lee Graham Parker Maik Hüttemann Daniel A. Rappolee Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency Stem Cell Research |
| title | Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency |
| title_full | Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency |
| title_fullStr | Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency |
| title_full_unstemmed | Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency |
| title_short | Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency |
| title_sort | hypoxic stress induces but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency |
| url | http://www.sciencedirect.com/science/article/pii/S1873506114000889 |
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