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Aspirin-Mediated Reset of Preeclamptic Placental Stem Cell Transcriptome – Implication for Stabilized Placental Function

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Abstract

Preeclampsia (PE) is a pregnancy-specific disease, occurring in ~ 2–10% of all pregnancies. PE is associated with increased maternal and perinatal morbidity and mortality, hypertension, proteinuria, disrupted artery remodeling, placental ischemia and reperfusion, and inflammation. The mechanism of PE pathogenesis remains unresolved explaining limited treatment. Aspirin is used to reduce the risk of developing PE. This study investigated aspirin’s effect on PE-derived placenta mesenchymal stem cells (P-MSCs). P-MSCs from chorionic membrane (CM), chorionic villi, membranes from the maternal and amniotic regions, and umbilical cord were similar in morphology, phenotype and multipotency. Since CM-derived P-MSCs could undergo long-term passages, the experimental studies were conducted with this source of P-MSCs. Aspirin (1 mM) induced significant functional and transcriptomic changes in PE-derived P-MSCs, similar to healthy P-MSCs. These include cell cycle quiescence, improved angiogenic pathways, and immune suppressor potential. The latter indicated that aspirin could induce an indirect program to mitigate PE-associated inflammation. As a mediator of activating the DNA repair program, aspirin increased p53, and upregulated genes within the basic excision repair pathway. The robust ability for P-MSCs to maintain its function with high dose aspirin contrasted bone marrow (M) MSCs, which differentiated with eventual senescence/aging with 100 fold less aspirin. This difference cautions how data from other MSC sources are extrapolated to evaluate PE pathogenesis. Dysfunction among P-MSCs in PE involves a network of multiple pathways that can be restored to an almost healthy functional P-MSC. The findings could lead to targeted treatment for PE.

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Data Availability

Data are available from Dr. Pranela Rameshwar (rameshwa@njms.rutgers.edu).

Code Availability

Not applicable.

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Funding

This work was supported by the Aryeh Foundation and NJCCR predoctoral fellow to LSS.

Author information

Author notes

  1. Matthew P. Romagano and Lauren S. Sherman contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Health, D–Maternal Fetal Medicine, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA

    Matthew P. Romagano & Shauna F. Williams

  2. Department of Medicine–Hematology/Oncology, Rutgers New Jersey Medical School, Newark, NJ, USA

    Lauren S. Sherman, Bobak Shadpoor, Sami Souayah, Sri Harika Pamarthi, Joshua Kra, Anupama Hood-Nehra & Pranela Rameshwar

  3. Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA

    Lauren S. Sherman, Bobak Shadpoor & Markos El-Far

  4. Rutgers Cancer Institute of New Jersey, Newark, NJ, USA

    Joshua Kra & Anupama Hood-Nehra

  5. Department of Biology, Rutgers University, Newark, NJ, USA

    Jean-Pierre Etchegaray

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Contributions

MPR collected the placenta and expand the P-MSCs in culture, conducted the experiments, wrote the manuscript and analyzed the data.

LSS expand P-MSCs and MSC (M) in culture, conducted the experiments, wrote the manuscript and analyzed the data.

BS wrote the manuscript, conducted the experiments.

ME-F analyzed the RNA-Seq, provided conceptual input, wrote the manuscript.

SS analyzed the RNA-Seq, conducted experiments, reviewed the manuscript.

SHP conducted the experiments, analyzed the data, wrote the manuscript.

JK took bone marrow aspirate and acquire informed consent, culture MSC (C), wrote the manuscript, provided conceptual input into experimental design.

AH-N: took bone marrow aspirate and acquire informed consent, culture MSC (C), wrote the manuscript, provided conceptual input into experimental design.

J-PE analyzed the data, provided conceptual input into the experimental design and wrote the manuscript.

SFW initiated the overall concept, wrote the paper, analyze the data.

PR provided the major conceptual design, oversee the experiment, trouble shoot, provided final data analyses, wrote the manuscript.

Corresponding authors

Correspondence to Shauna F. Williams or Pranela Rameshwar.

Ethics declarations

Ethics Approval

Rutgers Institutional Review Board approved this study (see method section).

Consent to Participate

Participating subjects signed the informed consent forms (see method section).

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Not applicable.

Conflicts of Interest/Competing Interests

The authors declare no conflict of interest.

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This work is in partial fulfillment for LSS doctoral thesis and MR fellowship thesis.

Supplementary Information

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Romagano, M.P., Sherman, L.S., Shadpoor, B. et al. Aspirin-Mediated Reset of Preeclamptic Placental Stem Cell Transcriptome – Implication for Stabilized Placental Function. Stem Cell Rev and Rep 18, 3066–3082 (2022). https://doi.org/10.1007/s12015-022-10419-8

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  • DOI: https://doi.org/10.1007/s12015-022-10419-8

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