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Editorial

New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells

1
Departments of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07804, Korea
2
Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul 03760, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(10), 5288; https://doi.org/10.3390/ijms22105288
Submission received: 13 May 2021 / Accepted: 14 May 2021 / Published: 18 May 2021
Mesenchymal stem cells (MSCs) are multipotent cells derived from various tissues including bone marrow and adipose tissues. MSCs have the capacity to differentiate into mesodermal lineages, including chondroblasts, osteoblasts, and adipocytes. In addition to bone marrow and adipose tissues, Wharton’s jelly, umbilical cord, fetal/neonatal tissues [1], dental pulp [2], and placenta [3] have been studied as sources of MSCs that can differentiate into various cell types with therapeutic properties. The clinical applications of MSCs are based on their unique stem cell properties, including the secretion of trophic factors and their proangiogenic, anti-inflammatory, immune-modulatory, and anti-oxidative stress activities. However, large-scale expansion of these cells for allogeneic therapies requires minimization of donor-dependent and bioprocess variabilities [4]. This Special Issue, entitled “New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells”, includes eight articles, four of which are review papers that discuss novel sources of MSCs and recent advances in the characterization and applications of MSCs. The articles in this issue provide insight into the therapeutic uses of MSCs and their derivatives, such as extracellular vesicles (EVs) and MSC spheroids.
Menstrual blood [5], tonsils [6], and induced pluripotent stem cells (iPSCs) [7] are also attracting attention as novel tissue sources for MSCs and are expected to be suitable as cell therapy products. The iPSC-derived MSCs have been applied to skin regeneration and skin rejuvenation [8,9], and menstrual blood-derived MSCs (MB-MSCs) have shown angiogenic potential similar to that of bone marrow-derived MSCs (BM-MSCs) [5,10]. Tonsil-derived stem cells have excellent proliferation and differentiation capabilities, and their clinical applications as therapeutic agents have been studied [6,11,12].
Over the past decade, MSCs have been proposed as a promising therapeutic treatment for various diseases. Many preclinical and clinical studies have described various strategies for effective MSC therapy, including decisions about the most (1) satisfactory cell type for each therapeutic application, (2) satisfactory culture conditions to ensure therapeutic effects, (3) suitable and effective methods for the mass production of these cells, and (4) appropriate functional tests for determining whether these biological products for each therapeutic indication have been developed to overcome the limitations of MSCs, such as heterogeneity and safety and handling issues [4].
To optimize the clinical applications, the approaches used to develop biological products based on the molecular properties of MSCs and their mechanisms of action are being studied. Among these approaches, the paracrine function of MSCs via the secretome, which involves conditioned media (CM), EVs, and exosomes, is considered to be representative [5,9,13,14,15,16,17]. The CM derived from BM-MSCs and MB-MSCs have been shown to be capable of stimulating tube-like formation of human umbilical vein endothelial cells [5]. CM derived from BM-MSCs, amniotic membrane MSCs, umbilical cord blood MSCs, and umbilical cord tissue MSCs (UC-MSCs) have been shown to be effective treatments in rodent models of bronchopulmonary dysplasia (BPD) [15]. Ramalingam et al. reported the therapeutic role of CM derived from neural-induced adipose tissue-derived MSCs (AD-MSCs) against rotenone-induced Parkinson’s disease-like impairments [14].
EVs of the MSC secretome can generate an encouraging alternative for exploiting MSC properties and can be classified as exosomes (30–120 nm in diameter), which originate within endosomal compartments called multivesicular bodies in the cell [4]. EVs from AD-MSCs have anti-photoaging potential and have been used in subcutaneous injections in mouse models of photoaging [9,17]. In addition, the capacity to inhibit inflammation, which is consistent with the main actions described for EVs in general [15,18], has been observed in animal BPD models. Transmission of cellular senescence and proinflammatory activation between MSCs and their EVs are involved in the development of inflamm-aging, which is associated with the degeneration of organs and tissues during aging [16]. Mato-Basalo et al. reported that treatment of senescent UC-MSCs with small inhibitors (e.g., JSH-23, MG-132, or curcumin) prevented cellular senescence and proinflammatory activation in MSCs, and paracrine and proinflammatory transmission by EVs through inhibition of the p65 pathway [16].
To advance the development of innovative stem cell therapies, priming [15,16,17,18,19] or genetic engineering of MSCs and biomaterial-based physical/structural modification [5,13,15] of MSCs have been studied. Treatment of AD-MSCs with fibronectin-derived peptide has been shown to improve their proliferation and differentiation into osteoblasts [19]. An improved therapeutic effect of BM-MSCs treated with recombinant erythropoietin in a rodent BPD model has also been reported [15,20]. In addition, genetic engineering techniques have been applied to induce insufficient endogenous factors or new proteins directly within MSCs [21]. Various MSCs have been used with genetic modification technology using RNA viruses, such as lentiviruses and retroviruses, and DNA viruses, including adenoviruses or adeno-associated viruses, and the preclinical results of these studies have been published [4]. The formation of spheroids that recover cell communication and provide a concertation gradient of external factors depending on the location, as observed in vivo, has been reported. These spheroids exhibit superior viability, self-renewal capacity, and differentiation potential compared with two-dimensional cells [13].
As presented in this issue, several biotechnology techniques have been developed to overcome the limitations noted in previous reports on the clinical applications of MSCs and to produce high-efficiency MSCs. MSCs and their products applied using these biotechnology techniques should focus on standardization to ensure the safety verification and cell quality control needed for practical clinical applications. The accumulated results of these studies will ultimately accelerate the development and practical clinical applications of high-efficiency MSCs and their product therapeutics.

Author Contributions

S.P. participated in the conceptualization and writing-original draft preparation. S.-C.J. participated in the conceptualization, funding acquisition, and writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by a grant from the Health Technology R&D Project (HI20C0039) of the Ministry of Health and Welfare, Republic of Korea, and an RP-Grant 2019 of Ewha Womans University.

Acknowledgments

We thank all authors for their high-quality papers.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Crisan, M.; Yap, S.; Casteilla, L.; Chen, C.-W.; Corselli, M.; Park, T.S.; Andriolo, G.; Sun, B.; Zheng, B.; Zhang, L.; et al. A Perivascular Origin for Mesenchymal Stem Cells in Multiple Human Organs. Cell Stem Cell 2008, 3, 301–313. [Google Scholar] [CrossRef] [Green Version]
  2. Gronthos, S.; Mankani, M.; Brahim, J.; Robey, P.G.; Shi, S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc. Natl. Acad. Sci. USA 2000, 97, 13625–13630. [Google Scholar] [CrossRef] [Green Version]
  3. Igura, K.; Zhang, X.; Takahashi, K.; Mitsuru, A.; Yamaguchi, S.; Takahashi, T. Isolation and characterization of mesenchymal progenitor cells from chorionic villi of human placenta. Cytotherapy 2004, 6, 543–553. [Google Scholar] [CrossRef] [PubMed]
  4. Fernández-Francos, S.; Eiro, N.; Costa, L.; Escudero-Cernuda, S.; Fernández-Sánchez, M.; Vizoso, F. Mesenchymal Stem Cells as a Cornerstone in a Galaxy of Intercellular Signals: Basis for a New Era of Medicine. Int. J. Mol. Sci. 2021, 22, 3576. [Google Scholar] [CrossRef]
  5. Patel, A.N.; Park, E.; Kuzman, M.; Benetti, F.; Silva, F.J.; Allickson, J.G. Multipotent Menstrual Blood Stromal Stem Cells: Isolation, Characterization, and Differentiation. Cell Transplant. 2008, 17, 303–311. [Google Scholar] [CrossRef] [Green Version]
  6. Oh, S.-Y.; Choi, Y.M.; Kim, H.Y.; Park, Y.S.; Jung, S.-C.; Park, J.-W.; Woo, S.-Y.; Ryu, K.-H.; Kim, H.S.; Jo, I. Application of Tonsil-Derived Mesenchymal Stem Cells in Tissue Regeneration: Concise Review. Stem Cells 2019, 37, 1252–1260. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Xu, M.; Shaw, G.; Murphy, M.; Barry, F. Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells Are Functionally and Genetically Different from Bone Marrow-Derived Mesenchymal Stromal Cells. Stem Cells 2019, 37, 754–765. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Nakayama, C.; Fujita, Y.; Matsumura, W.; Ujiie, I.; Takashima, S.; Shinkuma, S.; Nomura, T.; Abe, R.; Shimizu, H. The development of induced pluripotent stem cell-derived mesenchymal stem/stromal cells from normal human and RDEB epidermal keratinocytes. J. Dermatol. Sci. 2018, 91, 301–310. [Google Scholar] [CrossRef]
  9. Jo, H.; Brito, S.; Kwak, B.; Park, S.; Lee, M.-G.; Bin, B.-H. Applications of Mesenchymal Stem Cells in Skin Regeneration and Rejuvenation. Int. J. Mol. Sci. 2021, 22, 2410. [Google Scholar] [CrossRef]
  10. Santos, R.D.A.; Asensi, K.D.; De Barros, J.H.O.; de Menezes, R.C.S.; Cordeiro, I.R.; Neto, J.M.D.B.; Kasai-Brunswick, T.H.; Goldenberg, R.C.D.S. Intrinsic Angiogenic Potential and Migration Capacity of Human Mesenchymal Stromal Cells Derived from Menstrual Blood and Bone Marrow. Int. J. Mol. Sci. 2020, 21, 9563. [Google Scholar] [CrossRef] [PubMed]
  11. Jung, N.; Park, S.; Choi, Y.; Park, J.-W.; Bin Hong, Y.; Park, H.H.C.; Yu, Y.; Kwak, G.; Kim, H.S.; Ryu, K.-H.; et al. Tonsil-Derived Mesenchymal Stem Cells Differentiate into a Schwann Cell Phenotype and Promote Peripheral Nerve Regeneration. Int. J. Mol. Sci. 2016, 17, 1867. [Google Scholar] [CrossRef] [PubMed]
  12. Park, S.; Kim, J.Y.; Myung, S.; Jung, N.; Choi, Y.; Jung, S.-C. Differentiation of Motor Neuron-Like Cells from Tonsil-Derived Mesenchymal Stem Cells and Their Possible Application to Neuromuscular Junction Formation. Int. J. Mol. Sci. 2019, 20, 2702. [Google Scholar] [CrossRef] [Green Version]
  13. Seo, Y.; Kang, M.-J.; Kim, H.-S. Strategies to Potentiate Paracrine Therapeutic Efficacy of Mesenchymal Stem Cells in Inflammatory Diseases. Int. J. Mol. Sci. 2021, 22, 3397. [Google Scholar] [CrossRef] [PubMed]
  14. Ramalingam, M.; Jang, S.; Jeong, H.-S. Neural-Induced Human Adipose Tissue-Derived Stem Cells Conditioned Medium Ameliorates Rotenone-Induced Toxicity in SH-SY5Y Cells. Int. J. Mol. Sci. 2021, 22, 2322. [Google Scholar] [CrossRef] [PubMed]
  15. Goetz, M.; Kremer, S.; Behnke, J.; Staude, B.; Shahzad, T.; Holzfurtner, L.; Chao, C.-M.; Morty, R.; Bellusci, S.; Ehrhardt, H. MSC Based Therapies to Prevent or Treat BPD—A Narrative Review on Advances and Ongoing Challenges. Int. J. Mol. Sci. 2021, 22, 1138. [Google Scholar] [CrossRef]
  16. Mato-Basalo, R.; Morente-López, M.; Arntz, O.; van de Loo, F.; Fafián-Labora, J.; Arufe, M. Therapeutic Potential for Regulation of the Nuclear Factor Kappa-B Transcription Factor p65 to Prevent Cellular Senescence and Activation of Pro-Inflammatory in Mesenchymal Stem Cells. Int. J. Mol. Sci. 2021, 22, 3367. [Google Scholar] [CrossRef]
  17. Xu, P.; Xin, Y.; Zhang, Z.; Zou, X.; Xue, K.; Zhang, H.; Zhang, W.; Liu, K. Extracellular vesicles from adipose-derived stem cells ameliorate ultraviolet B-induced skin photoaging by attenuating reactive oxygen species production and inflammation. Stem Cell Res. Ther. 2020, 11, 1–14. [Google Scholar] [CrossRef]
  18. Harrell, C.R.; Jovicic, N.; Djonov, V.; Arsenijevic, N.; Volarevic, V. Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases. Cells 2019, 8, 1605. [Google Scholar] [CrossRef] [Green Version]
  19. Lee, E.-J.; Ahmad, K.; Pathak, S.; Lee, S.; Baig, M.; Jeong, J.-H.; Doh, K.-O.; Lee, D.-M.; Choi, I. Identification of Novel FNIN2 and FNIN3 Fibronectin-Derived Peptides That Promote Cell Adhesion, Proliferation and Differentiation in Primary Cells and Stem Cells. Int. J. Mol. Sci. 2021, 22, 3042. [Google Scholar] [CrossRef]
  20. Zhang, Z.-H.; Pan, Y.-Y.; Jing, R.-S.; Luan, Y.; Zhang, L.; Sun, C.; Kong, F.; Li, K.-L.; Wang, Y.-B. Protective effects of BMSCs in combination with erythropoietin in bronchopulmonary dysplasia-induced lung injury. Mol. Med. Rep. 2016, 14, 1302–1308. [Google Scholar] [CrossRef]
  21. Varkouhi, A.K.; Monteiro, A.P.T.; Tsoporis, J.N.; Mei, S.H.J.; Stewart, D.J.; Dos Santos, C.C. Genetically Modified Mesenchymal Stromal/Stem Cells: Application in Critical Illness. Stem Cell Rev. Rep. 2020, 16, 1–16. [Google Scholar] [CrossRef] [PubMed]
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Park, S.; Jung, S.-C. New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells. Int. J. Mol. Sci. 2021, 22, 5288. https://doi.org/10.3390/ijms22105288

AMA Style

Park S, Jung S-C. New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells. International Journal of Molecular Sciences. 2021; 22(10):5288. https://doi.org/10.3390/ijms22105288

Chicago/Turabian Style

Park, Saeyoung, and Sung-Chul Jung. 2021. "New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells" International Journal of Molecular Sciences 22, no. 10: 5288. https://doi.org/10.3390/ijms22105288

APA Style

Park, S., & Jung, S. -C. (2021). New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells. International Journal of Molecular Sciences, 22(10), 5288. https://doi.org/10.3390/ijms22105288

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