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Spatio-Temporal Metabolokinetics and Efficacy of Human Placenta-Derived Mesenchymal Stem/Stromal Cells on Mice with Refractory Crohn’s-like Enterocutaneous Fistula

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Abstract

Crohn’s disease (CD) with externally fistulizing openings indicates the aggressive and relapsing manifestation and results in undesirable long-term outcomes of patients. MSC-based approach combined with multidisciplinary strategy has mandated a redefinition of the administration and management of numerous recurrent and refractory diseases whereas the spatio-temporal evaluation of the metabolokinetics and efficacy of MSCs on intractable CD with enterocutaneous fistula (EF) are largely inaccessible and dauntingly complex. Herein, we primitively established dual-fluorescence expressing placenta-derived MSCs (DF-MSCs) and explored their multidimensional attributes, including cytomorphology, immunophenotying, multilineage differentiation and long-term proliferation, together with the recognition of bifluorescence intensity (BLI). Then, with the aid of in vivo living imaging, clinicopathological or inflammatory cytokine examinations and in vitro analyses, we systematically and meticulously dissected the metabolokinetics and curative effect of MSCs on mice with refractory Crohn’s-like EF (EF mice), together with revealing the underlying mechanism including reactive oxygen species (ROS) and neovascularization. Strikingly, the DF-MSCs exhibited stabilized BLI and biological properties. The spatio-temporal distribution and therapeutic process of MSCs in EF mice were intuitively delineated. Meanwhile, our data indicated the curative mechanisms of DF-MSCs by simultaneously downregulating ROS and accelerating neovascularization. Collectively, we systematically illuminated the spatio-temporal biofunction and mechanism of DF-MSCs on EF mice. Our findings have supplied new references for safety and effectiveness assessments as well as the establishment of guidelines for optimal administrations of MSC-based cytotherapy in preclinical studies, which collectively indicates the prospect of P-MSC administration in clinical trials during a wide spectrum of disease remodeling including the fistulizing CD.

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Acknowledgements

We thank Ying Chi, Yimeng Wei, Yi Yu, Zhibo Han, Zhihai Han, Dengke Liu, Rucai Zhan and Baiqing Dong for technical support or constructive suggestions. Also, we appreciate Gang Liu and Yanyan Xu in Tianjin Medical University for their kind help and technical support during the construction of mice model. The authors would like to thank the enterprise postdoctoral working station of Tianjin Chase Sun Pharmaceutical Co., Ltd. and Precision Medicine Division of Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., and Postdoctoral workstation of Wuqing development Zone in Tianjin city for their kind support.

Funding

This work was supported by grants from the National Natural Science Foundation of China (81770119), Project funded by China Postdoctoral Science Foundation (2019 M661033), Natural Science Foundation of Tianjin (19JCQNJC12500), Natural Science Foundation of Hebei (H2020206403), Natural Science Foundation of Shandong (2020, to LSZ), Science and Technology Project of Tianjin (17ZXSCSY00030), Nanyang Science and Technology Project of He-nan Province (JCQY012), Emergency project funded by Department of Science and Technology of Jiangxi Province (2020, to ZCH), Key project funded by Department of Science and Technology of Shangrao City (2020, to ZCH).

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  1. Huixing Hou and Leisheng Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, 300052, China

    Huixing Hou, Liyun Duan, Yuanyuan Liu & Xiaocang Cao

  2. The Postdoctoral Research Station, School of Medicine, Nankai University, Tianjin, 300071, China

    Leisheng Zhang & Zongjin Li

  3. State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People’s Republic of China

    Leisheng Zhang & Zhongchao Han

  4. Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd, Tianjin, 301700, China

    Leisheng Zhang & Zhongchao Han

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  1. Huixing Hou
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Contributions

H.H.: performed the experiments, collection and assembly of data; L.D., Y.L. and Z.H.: helped with collection and assembly of data; H.H., L.Z.: helped with the mice experiments; L.Z., Z.L. and X.C.: data analysis and interpretation, manuscript writing; L.Z. and X.C.: conception and design, final approval and revision of manuscript.

Corresponding authors

Correspondence to Leisheng Zhang, Zongjin Li or Xiaocang Cao.

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The authors declare that they have no conflict of interests.

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This experiment was approved by the Ethical Committee of Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Science and Peking Union Medical College (approval no. KT2019048-EC-1, KT2016011-EC-1) and in accordance with the Standard Operation Procedures (SOP) of the same facility.

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Hou, H., Zhang, L., Duan, L. et al. Spatio-Temporal Metabolokinetics and Efficacy of Human Placenta-Derived Mesenchymal Stem/Stromal Cells on Mice with Refractory Crohn’s-like Enterocutaneous Fistula. Stem Cell Rev and Rep 16, 1292–1304 (2020). https://doi.org/10.1007/s12015-020-10053-2

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