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Free Fatty Acids from Type 2 Diabetes Mellitus Serum Remodel Mesenchymal Stem Cell Lipids, Hindering Differentiation into Primordial Germ Cells

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Abstract

Type 2 diabetes mellitus (T2DM) adversely affects the essential characteristics of adipose tissue-derived mesenchymal stem cells (AdMSCs). Given that T2DM is associated with an altered serum free fatty acid (FFA) profile, we examined whether diabetic serum FFAs influence the viability, differentiation, and fatty acid composition of the major lipid fractions of human AdMSCs in vitro. Serum FFAs were isolated from 7 diabetic and 10 healthy nondiabetic female individuals. AdMSCs were cultured and differentiated into primordial germ cell-like cells (PGCLCs) in the presence of either diabetic or nondiabetic FFAs. Cell viability was assessed using trypan blue staining. Cell differentiation was evaluated by measuring the PGCLC transcriptional markers Blimp1 and Stella. Lipid fractionation and fatty acid quantification were performed using thin-layer chromatography and gas–liquid chromatography, respectively. Both diabetic and nondiabetic FFAs significantly reduced the viability of PGCLCs. The gene expression of both differentiation markers was significantly lower in cells exposed to diabetic FFAs than in those treated with nondiabetic FFAs. Saturated fatty acids were significantly increased and linoleic acid was significantly decreased in the cellular phospholipid fraction after exposure to diabetic FFAs. In contrast, monounsaturated fatty acids were reduced and linoleic acid was elevated in the cellular triglyceride fraction in response to diabetic FFAs. Such an altered serum FFA profile in patients with T2DM reduces the proliferation and differentiation potential of AdMSCs, presumably due to the aberrant distribution of fatty acids into cell phospholipids and triglycerides.

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Data Availability Statement

Data will be available from corresponding author on reasonable request.

Abbreviations

AdMSCs:

Adipose derived mesenchymal stem cells

DM:

Diabetes mellitus

DS:

Diabetic serum

FBS:

Fasting blood sugar

FFAs:

Free fatty acids

MSCs:

Mesenchymal stem cells

MUFAs:

Monounsaturated fatty acids

nDS:

Non diabetic serum

PUFAs:

Polyunsaturated fatty acids

SFAs:

Saturated fatty acids

PGCLC:

Primordial germ cell-like cell

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Funding

This work was supported by grants from Endocrine Research Center, Tabriz University of Medical Sciences and Tabriz University of Medical Sciences (numbers [59420] and [66852]) to AM. The last author is supported by fellowship programs from the Alexander von Humboldt Foundation. The graphical designs were created with BioRender.com.

Author information

Authors and Affiliations

  1. Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Zahra Norouzi & Mitra Niafar

  2. Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Zahra Norouzi, Reza Zarezadeh & Parisa Fayyazpour

  3. Student’s Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Zarezadeh

  4. Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Amir Mehdizadeh

  5. Department of Gynecologic Endocrinology and Fertility Disorders, Women’s Hospital, Ruprecht-Karls University of Heidelberg, Heidelberg, Germany

    Ariane Germeyer & Shabnam Fayezi

  6. Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Shabnam Fayezi

Authors
  1. Zahra Norouzi
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Contributions

Conceiving the study and designing the experiments, SF and AM; acquisition of funding, critical review and commentary, MN; providing human samples, ZN; performing the experiments and drafting the manuscript, RZ; statistical analysis, AG; supervision and planning. All authors participated in editing and have read and approved the manuscript.

Corresponding authors

Correspondence to Amir Mehdizadeh or Shabnam Fayezi.

Ethics declarations

Ethics Approval

This study was approved by the Ethics Committee of Tabriz University of Medical Sciences (Code: IR.TBZMED.REC.1400.011).

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Complete explanations of the study were given to the participants and informed consent was obtained.

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The authors affirm that human research participants provided informed consent for publication of all Figures and Tables.

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The authors have no relevant financial or non-financial interests to disclose.

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WHAT’S KNOWN?

  • The serum free fatty acid profile is altered in type 2 diabetes.

WHAT’S NEW?

  • The gene expression of both primordial germ cell-like cell differentiation markers significantly decreases in cells exposed to diabetic free fatty acids (FFAs).

  • Diabetic FFAs significantly increase saturated fatty acids and decrease linoleic acid in the phospholipid fraction.

  • Diabetic FFAs reduce monounsaturated fatty acids and increase linoleic acid in the triglyceride fraction.

Supplementary Information

Below is the link to the electronic supplementary material.

12010_2022_4204_MOESM1_ESM.docx

Supplementary file1 (DOCX 16 KB) Table S1. The primer sequences of the primordial germ cell-like cell differentiation markers.

12010_2022_4204_MOESM2_ESM.docx

Supplementary file2 (DOCX 14 KB) Table S2. Effects of diabetic and nondiabetic free fatty acids on the viability of primordial germ cell like cells.

12010_2022_4204_MOESM3_ESM.docx

Supplementary file3 (DOCX 14 KB) Table S3. Raw original data of fatty acid percentage or ratio of MSCs phospholipid and triglyceride fractions in the individually studied groups.

Figure S1

. Image of a thin-layer chromatography plate on which nondiabetic pooled whole serum (nDPWS) and lipid-depleted nondiabetic pooled serum (nDS) samples were run. The rectangles show the free fatty acid fractions in each serum sample.

High Resolution Image (TIF 188 KB)

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Norouzi, Z., Zarezadeh, R., Mehdizadeh, A. et al. Free Fatty Acids from Type 2 Diabetes Mellitus Serum Remodel Mesenchymal Stem Cell Lipids, Hindering Differentiation into Primordial Germ Cells. Appl Biochem Biotechnol 195, 3011–3026 (2023). https://doi.org/10.1007/s12010-022-04204-z

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