Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications

doi:10.1186/s12929-021-00725-7

Review

. 2021 Apr 14;28(1):28.

doi: 10.1186/s12929-021-00725-7.

Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications

Wei-Zhan Zhuang^#^{1

2

3}, Yi-Heng Lin^#^{1

4

5}, Long-Jyun Su⁶, Meng-Shiue Wu⁷, Han-Yin Jeng^{1

3}, Huan-Cheng Chang^{6

8}, Yen-Hua Huang^{9

10

11

12

13

14

15}, Thai-Yen Ling^{16

17}

Affiliations

¹ Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
² Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
³ TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
⁴ Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, 10041, Taiwan.
⁵ Department of Obstetrics and Gynecology, National Taiwan University Hospital Yunlin Branch, Yunlin, 64041, Taiwan.
⁶ Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan.
⁷ Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan.
⁸ Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106, Taiwan.
⁹ Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹⁰ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹¹ TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹² International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹³ Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹⁴ Comprehensive Cancer Center of Taipei Medical University, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹⁵ The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹⁶ Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan. tyling@ntu.edu.tw.
¹⁷ Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 100, Taiwan. tyling@ntu.edu.tw.

^# Contributed equally.

PMID: 33849537
PMCID: PMC8043779
DOI: 10.1186/s12929-021-00725-7

Review

Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications

Wei-Zhan Zhuang et al. J Biomed Sci. 2021.

. 2021 Apr 14;28(1):28.

doi: 10.1186/s12929-021-00725-7.

Authors

Affiliations

¹ Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
² Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
³ TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
⁴ Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, 10041, Taiwan.
⁵ Department of Obstetrics and Gynecology, National Taiwan University Hospital Yunlin Branch, Yunlin, 64041, Taiwan.
⁶ Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan.
⁷ Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan.
⁸ Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106, Taiwan.
⁹ Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹⁰ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹¹ TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹² International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹³ Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹⁴ Comprehensive Cancer Center of Taipei Medical University, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹⁵ The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan. rita1204@tmu.edu.tw.
¹⁶ Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan. tyling@ntu.edu.tw.
¹⁷ Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 100, Taiwan. tyling@ntu.edu.tw.

^# Contributed equally.

PMID: 33849537
PMCID: PMC8043779
DOI: 10.1186/s12929-021-00725-7

Abstract

Mesenchymal stem/stromal cells (MSCs) are a promising resource for cell-based therapy because of their high immunomodulation ability, tropism towards inflamed and injured tissues, and their easy access and isolation. Currently, there are more than 1200 registered MSC clinical trials globally. However, a lack of standardized methods to characterize cell safety, efficacy, and biodistribution dramatically hinders the progress of MSC utility in clinical practice. In this review, we summarize the current state of MSC-based cell therapy, focusing on the systemic safety and biodistribution of MSCs. MSC-associated risks of tumor initiation and promotion and the underlying mechanisms of these risks are discussed. In addition, MSC biodistribution methodology and the pharmacokinetics and pharmacodynamics of cell therapies are addressed. Better understanding of the systemic safety and biodistribution of MSCs will facilitate future clinical applications of precision medicine using stem cells.

Keywords: Cell therapy; Mesenchymal stem/stromal cell; Single cell imaging; Systemic safety; biodistribution.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
MSC sources and clinical indications in clinical studies. As of October 11, 2020, 1,242 registered studies were identified on clinicaltrials.gov by searching keywords “mesenchymal stem cell” or “mesenchymal stromal cell” (Additional file 1). After excluding studies with no longer available/ suspended/ temporarily not available/ terminated/ unknown/ withdrawn status, unknown phase information, and studies that did not use MSCs in their intervention arm, 639 studies remained. Nine of these 639 studies investigated MSCs from two tissue origins, generating a total of 648 studies for analysis. a Tissue origins of MSCs in clinical studies, b number of MSC-related clinical studies by medical specialty, and c the top 20 disease indications of MSC-related clinical studies

**Fig. 2**
Promotion and suppression effects of MSCs on different cancer types. Data analysis from published studies listed in Tables 4 and 5, but excluding engineered MSCs. *N.R.* not reported

**Fig. 3**
Schematic diagram of tumor promoting mechanisms of MSCs. MSCs influence cancer cells and immune cells to promote tumor cell proliferation, invasion, migration and metastasis. Secreted microRNA-containing exosomes, soluble factors, and contact-dependent signaling pathways are summarized

**Fig. 4**
Schematic diagram of tumor suppressing mechanisms of MSCs. MSCs suppress tumor progression predominantly by promoting tumor cell apoptosis, autophagy, and senescence; and by boosting immunity, anti-angiogenesis, and anti-tumor cell migration and invasion

**Fig. 5**
Workflow of fluorescent nanodiamond (FND)-labelled tracking platform and biodistribution analysis of FND-labelled pcMSCs. a The FND-labelled tracking platform for cell biodistribution analysis. This platform can provide analysis for transplanted cell localization, pharmacokinetics (PK), and pharmacodynamics (PD). FND-labelled cells are delivered through intravenous injection. The transplanted cells can be pinpointed to specific locations with background-free imaging by Leica SP8 microscopy using a time-gating technique. PK and PD analyses can be performed with a magnetic modulation fluorescence (MMF) machine after tissue/organ digestion. b Distribution of FND-labelled pcMSCs among different organs in a healthy mouse model. Experiments were repeated in triplicate and error bars represent the standard deviation

**Fig. 6**
Fluorescent nanodimond (FND)-labelled pcMSC biodistribution analysis in mouse model with a kidney ischemia–reperfusion injury. a Timeline of the ischemia–reperfusion kidney injury mouse model. The ischemia–reperfusion injury was created on the left-hand side kidney (L) in a mouse, then FND-labelled pcMSCs were injected through the portal vein. b Bodistribution of FND-labelled pcMSCs in healthy kidney mouse model. Experiments were repeated in triplicate and error bars represent the standard deviation of the measurements. c Biodistribution of FND-labelled pcMSCs in ischemia–reperfusion kidney injury mouse model. Experiments were repeated in triplicate and error bars represent the standard deviation of uncertainty. Data are presented as mean ± standard deviation. Data were analyzed using Student’s t-test. *P value of < 0.05. **P value of < 0.01. ***P value of < 0.001. ****P value of < 0.0001

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References

1. Aijaz A, Li M, Smith D, Khong D, LeBlon C, Fenton OS, et al. Biomanufacturing for clinically advanced cell therapies. Nat Biomed Eng. 2018;2(6):362–376. doi: 10.1038/s41551-018-0246-6. - DOI - PMC - PubMed
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[1] Aijaz A, Li M, Smith D, Khong D, LeBlon C, Fenton OS, et al. Biomanufacturing for clinically advanced cell therapies. Nat Biomed Eng. 2018;2(6):362–376. doi: 10.1038/s41551-018-0246-6. - DOI - PMC - PubMed

[2] Aijaz A, Li M, Smith D, Khong D, LeBlon C, Fenton OS, et al. Biomanufacturing for clinically advanced cell therapies. Nat Biomed Eng. 2018;2(6):362–376. doi: 10.1038/s41551-018-0246-6. - DOI - PMC - PubMed

[3] Friedenstein AJ, Piatetzky S, II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;16(3):381–390. - PubMed

[4] Friedenstein AJ, Piatetzky S, II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;16(3):381–390. - PubMed

[5] Diehl R, Ferrara F, Müller C, Dreyer AY, McLeod DD, Fricke S, et al. Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches. Cell Mol Immunol. 2017;14(2):146–179. doi: 10.1038/cmi.2016.39. - DOI - PMC - PubMed

[6] Diehl R, Ferrara F, Müller C, Dreyer AY, McLeod DD, Fricke S, et al. Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches. Cell Mol Immunol. 2017;14(2):146–179. doi: 10.1038/cmi.2016.39. - DOI - PMC - PubMed

[7] Martin I, Galipeau J, Kessler C, Le Blanc K, Dazzi F. Challenges for mesenchymal stromal cell therapies. Sci Transl Med. 2019 doi: 10.1126/scitranslmed.aat2189. - DOI - PubMed

[8] Martin I, Galipeau J, Kessler C, Le Blanc K, Dazzi F. Challenges for mesenchymal stromal cell therapies. Sci Transl Med. 2019 doi: 10.1126/scitranslmed.aat2189. - DOI - PubMed

[9] Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230–247. doi: 10.1097/00007890-196803000-00009. - DOI - PubMed

[10] Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230–247. doi: 10.1097/00007890-196803000-00009. - DOI - PubMed

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Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications

Affiliations

Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications

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Abstract

Conflict of interest statement

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