Skip to main content

Advertisement

SpringerLink
Log in

Statistical study of clinical trials with stem cells and their function in skin wound

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Mesenchymal stem cells (MSCs) have been known as a reliable and effective source to repair damaged tissues. The differentiation and self-renewal ability, easy access, immune system modulation capability, and important role in the process of repairing wounds have caused using these cells extensively in wound healing. In this review study, the role of MSCs is debated about different diseases especially in repairing skin wounds. This review article was obtained from 75 basic and trial articles on the PubMed, Google Scholar, and Clinical Trials databases between 2000 and 2022. MSCs are capable of migrating to the wound site and are effective in all stages of wound healing. These cells differentiate into skin cells and also inhibit inflammatory responses, proliferation, and differentiation cells through paracrine messages. They stimulate locally resident precursors, leading to angiogenesis, epithelial regeneration, and granular tissue formation. During maturation stages, these cells decrease fibrosis tissue formation and wound contraction and increase collagen expression and wound tensile strength. The molecular factors of the lesion site change function of these cells and cause MSCs to create a wound healing microenvironment instead of a fibrotic microenvironment. Currently, significant advances have been achieved in the delivery of MSCs to wound sites. These cells are injected intravenously or intradermally, with or without a scaffold. They are also used in the form of spray or hydrogels. Furthermore, the extracellular vesicles and the synergistic environment of these cells alone are effective. Forthcoming studies could lead to more effective treatment strategies for the use of MSCs in wound healing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

References

  • al HE (2012) Isolation of mouse mesenchymal stem cells on the basis of expression of Sca-1 and PDGFR-α. Nature Prot 7(12):2103–2111

  • Andrzejewska A, Lukomska B, Janowski M (2019) Concise review: mesenchymal stem cells: from roots to boost. Stem cells 37(7):855–864

    Article  PubMed  Google Scholar 

  • Borowiec A-S, Delcourt P, Dewailly E, Bidaux G (2013) Optimal differentiation of in vitro keratinocytes requires multifactorial external control. PLoS One 8(10):e77507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brandau S, Jakob M, Bruderek K, Bootz F, Giebel B, Radtke S, ... Lang S (2014) Mesenchymal stem cells augment the antibacterial activity of neutrophil granulocytes. PLoS One 9(9), e106903

  • Brohem CA, da Silva Cardeal LB, Tiago M, Soengas MS, de Moraes Barros SB, Maria-Engler SS (2011) Artificial skin in perspective: concepts and applications. Pigment Cell Melanoma Res 24(1):35–50

    Article  PubMed  Google Scholar 

  • Brown JM, Nemeth K, Kushnir-Sukhov NM, Metcalfe DD, Mezey E (2011) Bone marrow stromal cells inhibit mast cell function via a COX2-dependent mechanism. Clin Experimen Aller 41(4):526–534

    Article  CAS  Google Scholar 

  • Caplan H, Olson SD, Kumar A, George M, Prabhakara KS, Wenzel P, ... Kamhieh-Milz J (2019) Mesenchymal stromal cell therapeutic delivery: translational challenges to clinical application. Front Immunol 10, 1645

  • Carvalho IC, Mansur HS (2017) Engineered 3D-scaffolds of photocrosslinked chitosan-gelatin hydrogel hybrids for chronic wound dressings and regeneration. Mat Sci Eng 78:690–705

    Article  CAS  Google Scholar 

  • Chaudhari AA, Vig K, Baganizi DR, Sahu R, Dixit S, Dennis V, ... Pillai SR (2016) Future prospects for scaffolding methods and biomaterials in skin tissue engineering: a review. Int J Mol Sci 17(12), 1974

  • Chen JS, Wong VW, Gurtner GC (2012) Therapeutic potential of bone marrow-derived mesenchymal stem cells for cutaneous wound healing. Front Immunol 3:192

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen Q-H, Wu F, Liu L, Chen H-B, Zheng R-Q, Wang H-L, Yu L-N (2020) Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro. Stem Cell Res Therapy 11(1):1–11

    Article  Google Scholar 

  • De Becker A, Riet IV (2016) Homing and migration of mesenchymal stromal cells: how to improve the efficacy of cell therapy? World J Stem Cells 8(3):73–87. https://doi.org/10.4252/wjsc.v8.i3.73

    Article  PubMed  PubMed Central  Google Scholar 

  • Eggenhofer E, Benseler V, Kroemer A, Popp F, Geissler E, Schlitt H, ... Hoogduijn M (2012) Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol 3, 297

  • Eiro N, Fraile M, Fernández-Francos S, Sánchez R, Costa LA, Vizoso FJ (2021) Importance of the origin of mesenchymal (stem) stromal cells in cancer biology:“alliance” or “war” in intercellular signals. Cell Bioscie 11(1):1–19

    Article  Google Scholar 

  • Fan L, Hu C, Chen J, Cen P, Wang J, Li L (2016) Interaction between mesenchymal stem cells and B-cells. Int J Mol Sci 17(5):650

    Article  PubMed  PubMed Central  Google Scholar 

  • Ferdowsi Khosroshahi A, Soleimani Rad J, Kheirjou R, Roshangar B, Rashtbar M, Salehi R, Roshangar L (2020) Adipose tissue-derived stem cells upon decellularized ovine small intestine submucosa for tissue regeneration: an optimization and comparison method. J Cell Physiol 235(2):1556–1567

    Article  CAS  PubMed  Google Scholar 

  • Frykberg RG, Banks J (2015) Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle) 4(9):560–582. https://doi.org/10.1089/wound.2015.0635

    Article  PubMed  Google Scholar 

  • Fuloria S, Subramaniyan V, Dahiya R, Dahiya S, Sudhakar K, Kumari U, Sekar M (2021) Mesenchymal stem cell-derived extracellular vesicles: regenerative potential and challenges. Biology 10(3):172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garzón I, Miyake J, González-Andrades M, Carmona R, Carda C, Sánchez-Quevedo MD, Campos A, Alaminos M (2013) Wharton’s jelly stem cells: a novel cell source for oral mucosa and skin epithelia regeneration. Stem Cells Translational Med 2(8):625–632

  • Glennie S, Soeiro I, Dyson J, Lam E, Dazzi F (2005) Mesenchymal stem cells induce division arrest anergy of activated T cells. Biol Blood Marrow Transplant 11(2):1

    Article  Google Scholar 

  • Heher P, Mühleder S, Mittermayr R, Redl H, Slezak P (2018) Fibrin-based delivery strategies for acute and chronic wound healing. Adv Drug Delivery Rev 129:134–147

    Article  CAS  Google Scholar 

  • Hu MS, Borrelli MR, Lorenz HP, Longaker MT, Wan DC (2018) Mesenchymal stromal cells and cutaneous wound healing: a comprehensive review of the background, role, and therapeutic potential. Stem Cells Int 2018

  • Huang Y-Z, Gou M, Da L-C, Zhang W-Q, Xie H-Q (2020) Mesenchymal stem cells for chronic wound healing: current status of preclinical and clinical studies. Tissue Eng Part B Rev 26(6):555–570

    Article  CAS  PubMed  Google Scholar 

  • Ishihara S, Ponik SM, Haga H (2017) Mesenchymal stem cells in breast cancer: response to chemical and mechanical stimuli. Oncoscience 4(11–12):158–159. https://doi.org/10.18632/oncoscience.381

    Article  PubMed  PubMed Central  Google Scholar 

  • Jun JI, Lau LF (2010) Cellular senescence controls fibrosis in wound healing. Aging (Albany NY) 2(9):627–631. https://doi.org/10.18632/aging.100201

    Article  CAS  PubMed  Google Scholar 

  • Kanji S, Das H (2017) Advances of stem cell therapeutics in cutaneous wound healing and regeneration. Mediators Inflamm 2017

  • Kehl D, Generali M, Mallone A, Heller M, Uldry AC, Cheng P, ... Weber B (2019) Proteomic analysis of human mesenchymal stromal cell secretomes: a systematic comparison of the angiogenic potential. 4, 8. https://doi.org/10.1038/s41536-019-0070-y

  • Keshtkar S, Azarpira N, Ghahremani MH (2018) Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. Stem Cell Res Ther 9(1):1–9

    Google Scholar 

  • Kobolak J, Dinnyes A, Memic A, Khademhosseini A, Mobasheri A (2016) Mesenchymal stem cells: identification, phenotypic characterization, biological properties and potential for regenerative medicine through biomaterial micro-engineering of their niche. Methods 99:62–68

    Article  CAS  PubMed  Google Scholar 

  • Kuca-Warnawin E, Olesińska M, Szczȩsny P, Kontny E (2022) Impact and possible mechanism (s) of adipose tissue-derived mesenchymal stem cells on T cell proliferation in patients with rheumatic disease. Front Physiol 2464

  • Kulus M, Sibiak R, Stefańska K, Zdum M, Wieczorkiewicz M, Piotrowska-Kempisty H, ... Zabel M (2021) Mesenchymal stem/stromal cells derived from human and animal perinatal tissues—origins, characteristics, signaling pathways, and clinical trials. Cells 10(12), 3278

  • Li J, Sen GL (2015) Generation of genetically modified organotypic skin cultures using devitalized human dermis. JoVE (J Visual Exp)(106), e53280

  • Li M, Ma J, Gao Y, Dong M, Zheng Z, Li Y, ... Yang L (2020) Epithelial differentiation of human adipose-derived stem cells (hASCs) undergoing three-dimensional (3D) cultivation with collagen sponge scaffold (CSS) via an indirect co-culture strategy. Stem Cell Res Therapy 11(1), 1-16

  • Li P, Gong Z, Shultz LD, Ren G (2019a) Mesenchymal stem cells: from regeneration to cancer. Pharmacol Ther 200:42–54

  • Li X, Shang B, Li Y-N, Shi Y, Shao C (2019b) IFNγ and TNFα synergistically induce apoptosis of mesenchymal stem/stromal cells via the induction of nitric oxide. Stem Cell Res Ther 10(1):1–11

  • Lin W, Xu L, Zwingenberger S, Gibon E, Goodman SB, Li G (2017) Mesenchymal stem cells homing to improve bone healing. J Orthop Translat 9:19–27. https://doi.org/10.1016/j.jot.2017.03.002

    Article  PubMed  PubMed Central  Google Scholar 

  • Lu D, Xu Y, Liu Q, Zhang Q (2021) Mesenchymal stem cell-macrophage crosstalk and maintenance of inflammatory microenvironment homeostasis. Front Cell Develop Biol 1628

  • Maleki M, Ghanbarvand F, Behvarz MR, Ejtemaei M, Ghadirkhomi E (2014) Comparison of mesenchymal stem cell markers in multiple human adult stem cells. Int J Stem Cells 7(2):118–126

    PubMed  PubMed Central  Google Scholar 

  • Maqbool M, Algraittee SJR, Boroojerdi MH, Sarmadi VH, John CM, Vidyadaran S, Ramasamy R (2020) Human mesenchymal stem cells inhibit the differentiation and effector functions of monocytes. Innate Immunity 26(5):424–434. https://doi.org/10.1177/1753425919899132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martín Piedra MÁ, Alfonso-Rodríguez CA, Zapater Latorre A, Durand-Herrera D, Chato Astrain J, Campos F, ... Garzón Bello IJ (2019) Effective use of mesenchymal stem cells in human skin substitutes generated by tissue engineering

  • Melzer C, Yang Y, Hass R (2016) Interaction of MSC with tumor cells. Cell Commun Signal 14(1):1–12

    Article  Google Scholar 

  • Mezey É, Nemeth K (2015) Mesenchymal stem cells and infectious diseases: smarter than drugs. Immunol Letters 168(2):208–214

    Article  CAS  Google Scholar 

  • Mishra VK, Shih H-H, Parveen F, Lenzen D, Ito E, Chan T-F, Ke L-Y (2020) Identifying the therapeutic significance of mesenchymal stem cells. Cells 9(5):1145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montalbano G, Toumpaniari S, Popov A, Duan P, Chen J, Dalgarno K, ... Ferreira A (2018) Synthesis of bioinspired collagen/alginate/fibrin based hydrogels for soft tissue engineering. Mater Sci Eng 91, 236-246

  • Müller L, Tunger A, Wobus M, von Bonin M, Towers R, Bornhäuser M, ... Schmitz M (2021) Immunomodulatory properties of mesenchymal stromal cells: an update. Front Cell and Develop Biol 9. https://doi.org/10.3389/fcell.2021.637725

  • Pang SHM, D’Rozario J, Mendonca S, Bhuvan T, Payne NL, Zheng D, ... Powell D (2021) Mesenchymal stromal cell apoptosis is required for their therapeutic function. Nature Commun 12(1), 1-19

  • Rasmussen C, Thomas-Virnig C, Allen-Hoffmann BL (2012) Classical human epidermal keratinocyte cell culture. In Epithelial cell culture protocols (pp. 161-175): Springer

  • Rezaee R, Verdi J, Sadeghi M, Soleymanha M, Mirzaei M, Mobayen MR, Kianoush A (2022) The application of human Wharton’s jelly mesenchymal stem cells in wound healing: a narrative review. J Curr Biomed Rep

  • Roshangar L, Rad JS, Kheirjou R,  Khosroshahi AF (2021) Using 3D‐bioprinting scaffold loaded with adipose‐derived stem cells to burns wound healing. J Tissue Eng Regen Med

  • Séguier S, Tartour E, Guérin C, Couty L, Lemitre M, Lallement L, ... Badoual C (2013) Inhibition of the differentiation of monocyte-derived dendritic cells by human gingival fibroblasts. PLoS One 8(8), e70937

  • Shahrokhi S, Arno A, Jeschke MG (2014) The use of dermal substitutes in burn surgery: acute phase. Wound Repair Regen 22(1):14–22

    Article  PubMed  Google Scholar 

  • Shook BA, Wasko RR, Mano O, Rutenberg-Schoenberg M, Rudolph MC, Zirak B, ... Rezza A (2020) Dermal adipocyte lipolysis and myofibroblast conversion are required for efficient skin repair. Cell Stem Cell 26(6), 880-895. e886

  • Sivaraj D, Chen K, Chattopadhyay A, Henn D, Wu W, Noishiki C, ... Bonham CA (2021) Hydrogel scaffolds to deliver cell therapies for wound healing. Front Bioeng Biotechnol 9, 660145

  • Soland MA, Bego M, Colletti E, Zanjani ED, St. Jeor S, Porada CD, Almeida-Porada G (2013) Mesenchymal stem cells engineered to inhibit complement-mediated damage. PLoS One 8(3):e60461

  • Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L (2006) Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 107(4):1484–1490

    Article  CAS  PubMed  Google Scholar 

  • Tottoli EM, Dorati R, Genta I, Chiesa E, Pisani S, Conti B (2020) Skin wound healing process and new emerging technologies for skin wound care and regeneration. Pharmaceutics 12(8):735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsutsui TW (2020) Dental pulp stem cells: advances to applications. Stem Cells Cloning: Adv Appl 13:33

    Google Scholar 

  • Tu Z, Li Q, Bu H, Lin F (2010) Mesenchymal stem cells inhibit complement activation by secreting factor H. Stem Cells Develop 19(11):1803–1809

    Article  CAS  Google Scholar 

  • Ullah I, Subbarao RB, Rho GJ (2015) Human mesenchymal stem cells-current trends and future prospective. Biosci Rep 35(2)

  • Ullah M, Liu DD, Thakor AS (2019) Mesenchymal stromal cell homing: mechanisms and strategies for improvement. iScience 15, 421-438. https://doi.org/10.1016/j.isci.2019.05.004

  • Urciuolo F, Casale C, Imparato G, Netti PA (2019) Bioengineered skin substitutes: the role of extracellular matrix and vascularization in the healing of deep wounds. J Clin Med 8(12):2083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Via AG, Frizziero A, Oliva F (2012) Biological properties of mesenchymal stem cells from different sources. Muscles, ligaments and tendons journal 2(3):154

    PubMed  Google Scholar 

  • Vig K, Chaudhari A, Tripathi S, Dixit S, Sahu R, Pillai S, ... Singh SR (2017) Advances in skin regeneration using tissue engineering. Int J Mol Sci 18(4), 789

  • Watt SM, Gullo F, van der Garde M, Markeson D, Camicia R, Khoo CP, Zwaginga JJ (2013) The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential. British Med Bull 108(1):25–53. https://doi.org/10.1093/bmb/ldt031

    Article  Google Scholar 

  • Weiss ARR, Dahlke MH (2019) Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Front Immunol 10. https://doi.org/10.3389/fimmu.2019.01191

  • Wu C, Chen L, Huang Y-Z, Huang Y, Parolini O, Zhong Q, ... Deng L (2018) Comparison of the proliferation and differentiation potential of human urine-, placenta decidua basalis-, and bone marrow-derived stem cells. Stem Cells Int 2018

  • Wu Y, Peng Y, Gao D, Feng C, Yuan X, Li H, ... Fu X (2015) Mesenchymal stem cells suppress fibroblast proliferation and reduce skin fibrosis through a TGF-β3-dependent activation. Int J Lower Extremity Wounds 14(1), 50-62

  • Xu F, Dawson C, Lamb M, Mueller E, Stefanek E, Akbari M, Hoare T (2022) Hydrogels for tissue engineering: addressing key design needs toward clinical translation. Front Bioeng Biotechnol 10

  • Zhang J, Huang X, Wang H, Liu X, Zhang T, Wang Y, Hu D (2015) The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. Stem Cell Res Ther 6(1):1–7

    Article  Google Scholar 

  • Zupan J (2021) Mesenchymal stem/stromal cells and fibroblasts: their roles in tissue injury and regeneration, and age-related degeneration. Fibroblasts—Adv Inflammation, Autoimmunity and Cancer 1-25

Download references

Author information

Authors and Affiliations

  1. Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Linda Mohammadzadeh Boukani

  2. Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran

    Rana Ferdowsi Khosroshahi & Seddigheh Alizadeh Kh.

  3. Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Morteza Rashtbar

  4. Imam Reza General Hospital & Stem Cell Research, Tabriz University of Medical Sciences, Tabriz, Iran

    Ahad Ferdowsi Khosroshahi

Authors
  1. Linda Mohammadzadeh Boukani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rana Ferdowsi Khosroshahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seddigheh Alizadeh Kh.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Morteza Rashtbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahad Ferdowsi Khosroshahi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Corresponding and critical revisions: A. Ferdowsi Kh.; data collection and analysis: S. Alizadeh Kh. and R. Ferdowsi Kh.; and designing of the study and manuscript drafting: M. Rashtbar, L. Mohammadzadeh B., and R. Ferdowsi Kh.

Corresponding author

Correspondence to Ahad Ferdowsi Khosroshahi.

Ethics declarations

Ethical approval

No approval of research ethics committees was required to accomplish the goals of this study because experimental work was conducted with an unregulated invertebrate species.

Informed consent

This is not applicable.

Conflict of interest

The authors have no conflicts of interest to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boukani, L.M., Khosroshahi, R.F., Kh., S.A. et al. Statistical study of clinical trials with stem cells and their function in skin wound. Cell Tissue Res 393, 217–228 (2023). https://doi.org/10.1007/s00441-023-03793-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-023-03793-3

Keywords

Search

Navigation