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Adipose-derived Mesenchymal Stem Cells are Ideal for the Cell-based Treatment of Refractory Wounds: Strong Potential for Angiogenesis

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Abstract

Although Mesenchymal Stem Cells (MSCs)-based therapy has been proposed as a promising strategy for the treatment of chronic lower-extremity ulcers, their optimal sources, amounts, and delivery methods are urgently needed to be determined. In this study, we compared the heterogeneity of the human MSCs derived from bone marrow (BMSCs), umbilical cord (UCMSCs), and adipose tissue (ADSCs) in accelerating wound healing and promoting angiogenesis and explored the underlying mechanism. Briefly, a diabetic rat model with a full-thickness cutaneous wound on the dorsal foot was developed. The wound was topically administered with three types of MSCs. Additionally, we carried out in vitro and in vivo analysis of the angiogenic properties of the MSCs. Moreover, the molecular mechanism of the heterogeneity of the MSCs derived from the three tissues was explored by transcriptome sequencing. When compared with the BMSCs- and UCMSCs-treated groups, the ADSCs-treated group exhibited markedly accelerated healing efficiency, characterized by increased wound closure rates, enhanced angiogenesis, and collagen deposition at the wound site. The three types of MSCs formed three-dimensional capillary-like structures and promoted angiogenesis in vitro and in vivo, with ADSCs exhibiting the highest capacity for tube formation and pro-angiogenesis. Furthermore, transcriptome sequencing revealed that ADSCs had higher expression levels of angiogenesis-associated genes. Our findings indicate that MSCs-based therapy accelerates the healing of ischemia- and diabetes-induced lower-extremity ulcers and that adipose tissue-derived MSCs might be ideal for therapeutic angiogenesis and treatment of chronic ischemic wounds.

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Data Availability

The data and materials used to support the findings of this study are available from the corresponding author upon request.

Code Availability

Not applicable.

Abbreviations

ACVRL1:

Activin A receptor like type 1

ADSCs:

Adipose-derived mesenchymal stem cells

BMSCs:

Bone marrow mesenchymal stem cells

CCK-8:

Cell counting kit-8

CD29:

Cluster of differentiation 29

CD31:

Cluster of differentiation 31

CD34:

Cluster of differentiation 34

CD44:

Cluster of differentiation 44

CD45:

Cluster of differentiation 45

CD90:

Cluster of differentiation 90

CTSH:

Cathepsin H

DEGs:

Differentially expressed genes

ECs:

Endothelial cells

EMT:

Epithelial to mesenchymal transition

FPKM:

Fragments per kilobase of transcript per millions mapped reads

GO:

Gene Ontology

GSEA:

Gene set enrichment analysis

H&E:

Hematoxylin and eosin

IHC:

Immunohistochemistry

JAK1:

Janus Kinase 1

KEGG:

Kyoto Encyclopedia of Genes and Genomes

LG-DMEM:

Low glucose Dulbecco’s modified Eagle’s medium

MSCs:

Mesenchymal stem cells

OD:

Optical density

OLGs:

Overlapping genes

PAS:

Periodic acid-Schiff

PCA:

Principal components analysis

PFA:

Paraformaldehyde

RUNX1:

Runt-related transcription factor-1

SFRP2:

Secreted frizzled related-protein 2

STZ:

Streptozotocin

UCMSCs:

Umbilical cord mesenchymal stem cells

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Acknowledgements

Not applicable.

Funding

This work was supported by National Nature and Science Foundation of P.R. China (No.81871563, 82102345), Medical Research Foundation of Guangdong Province (A2021165), Fundamental Research Funds for the Central Universities (21619350), Guangdong Basic and Applied Basic Research Foundation (2019A1515110161, 2022A1515110940), Funding by Science and Technology Projects in Guangzhou (202201020002, 202201020004, 202201020468), Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University, China (No. JNU1AF-CFTP-2022-a01231, No. JNU1AF-CFTP-2022-a01208), Guangdong Provincial Key Areas R&D Programs (2022B1111080007), Special fund of Foshan Summit plan (No.2019D008), Medical Research Fund of Guangdong Province (No. A2020322), Research Grant of Key Laboratory of Regenerative Medicine, Ministry of Education, Jinan University (No: ZSYXM202209), China Postdoctoral Science Foundation (2022M721348).

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Author notes

  1. Yingxuan Cao and Jianxin Yan contributed equally to this work.

Authors and Affiliations

  1. Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China

    Yingxuan Cao, Jianxin Yan, Zhiqin Dong, Xiao Jiang & Hongwei Liu

  2. Innovative Technology Research Institute of Plastic Surgery, Guangzhou, 510630, People’s Republic of China

    Yingxuan Cao, Jianxin Yan, Zhiqin Dong, Xiao Jiang & Hongwei Liu

  3. Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou, 510632, People’s Republic of China

    Yingxuan Cao, Jianxin Yan, Zhiqin Dong, Xiao Jiang & Hongwei Liu

  4. Department of Burn Surgery, The First People’s Hospital of Foshan, Foshan, 528000, China

    Jingru Wang

  5. Dalton Cardiovascular Research Center, Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, 65211, USA

    Taixing Cui

  6. Department of Wound Repair, Institute of Wound Repair and Regeneration Medicine, Southern University of Science and Technology Hospital, Southern University of Science and Technology School of Medicine, Shenzhen, 518055, China

    Yuesheng Huang

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Contributions

YXC: Provision of study material or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; JXY: Collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; ZQD: Data analysis and interpretation, manuscript writing, final approval of manuscript; JRW, XJ: Financial support, final approval of manuscript; TXC: Conception and design, data analysis and interpretation, final approval of manuscript; YSH: Financial support, final approval of manuscript, final approval of manuscript; HWL: Conception and design, financial support, administrative support, manuscript writing, final approval of manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Taixing Cui, Yuesheng Huang or Hongwei Liu.

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Ethics Approval

The study was performed in accordance with the Declaration of Helsinki principles and was approved by the Medical Ethics Committee of the First Affiliated Hospital of Jinan University. The animal experiment protocol was approved by the Laboratory Animal Ethics Committee of Jinan University and performed following institutional guidelines.

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Informed consent was obtained from all individual participants included in the study.

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12015_2023_10641_MOESM1_ESM.png

Supplementary Material 1: Figure S1. MSC migration and proliferation capacity. (A) Scratch assay to detect the migration of BMSCs, UCMSCs, and ADSCs. (B) Quantitative analysis of wound closure rate. (C) CCK-8 assay at 1, 2, 3, 4, and 5 days of culture showing the proliferation of BMSCs, UCMSCs, and ADSCs. Data are presented as the mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001

12015_2023_10641_MOESM2_ESM.png

Supplementary Material 2: Figure S2. The top 20 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway terms of positive regulation of angiogenesis-associated differentially expressed genes (DEGs)

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Cao, Y., Yan, J., Dong, Z. et al. Adipose-derived Mesenchymal Stem Cells are Ideal for the Cell-based Treatment of Refractory Wounds: Strong Potential for Angiogenesis. Stem Cell Rev and Rep 20, 313–328 (2024). https://doi.org/10.1007/s12015-023-10641-y

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