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Mesenchymal Stem Cell 2.0: Greater Opportunities for Applications in Human Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 11266

Special Issue Editor

Prof. Dr. Steve Oh

E-Mail Website
Guest Editor
Stem Cell Bioprocessing, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore
Interests: stem cell bioprocessing; cell therapy; red blood cells; human induced pluripotent stem cells; reprogramming

Special Issue Information

Dear Colleagues,

Mesenchymal stromal cells (MSCs), are self-renewable cells that can be sourced from different tissues, such as the umbilical cord, bone marrow, adipose and fetal tissue. While the first generation MSC over the last 30 years has had a few successes and several late-stage clinical trials, no major clinical impact has yet been made unlike in the immunotherapy space. The reasons for this lack of success could be multi-factorial. The variable source of tissues from heterogeneous donors are parameters that need better identification, selection and control. Specific therapeutic properties have to be genetically engineered into the MSC to provide enhanced functions against a given disease. Therefore, various research teams around the world are developing MSC 2.0 which is the equivalent of engineering MSC to function with improved properties likened to CAR-T cells. The processes in manufacturing and banking such as microcarriers, bioreactors, cell harvesting technologies as well as defined growth media for culture is another set of variables that can be better controlled as the industry moves away from plasticware. To do so, better tools and analytics for online detection of cell quality, potency and safety have to be built to monitor the processes in order to allow adaptive changes to be made during biomanufacturing.

The therapeutic effect of MSCs can also be mediated via paracrine effects through releasing extracellular vesicles (EVs) like exosomes and microvesicles as well as secreting soluble factors. Engineering properties such as proteins, mRNA, miRNA and receptors expression into the EVs secreted by MSC 2.0 would boost their functions. Finally, better methods for scale up production, harvesting of the cells, purification of the EVs, along with new technologies for detection and purification of EVs are coming soon. This issue welcomes experts working in these various disciplines below to submit papers under cellular or molecular level, in order to realise the huge potential of MSC 2.0 for applications.

  1. Identification and selection of Mesenchymal Stromal Cells (MSC) 2.0 against human disorders.
  2. Engineering MSC for precision medicine.
  3. Extracellular vesicles secreting Medicinal Secreting Cells.
  4. Serum free media and microcarriers for MSC 2.0.
  5. Bioprocessing solutions for MSC and EVs: novel upstream and downstream processes.
  6. Innovative devices and analytics for detection of cell quality, potency and safety.

Prof. Dr. Steve Oh
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mesenchymal stromal cells (MSCs)
  • MSC 2.0
  • microcarriers
  • bioreactors
  • extracellular vesicles (EVs)
  • precision medicine
  • therapeutic effects on human diseases
  • mechanisms

Published Papers (6 papers)

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Research

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14 pages, 3624 KiB  
Article
Inhibition of Gap Junction Formation Prior to Implantation of Bone Marrow-Derived Mesenchymal Cells Improves Function in the Ischemic Myocardium
by Santipongse Chatchavalvanich, Robert A. Boomsma, Jack M. Tietema and David L. Geenen
Int. J. Mol. Sci. 2023, 24(11), 9653; https://doi.org/10.3390/ijms24119653 - 02 Jun 2023
Viewed by 1142
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSC) are reported to induce beneficial effects in the heart following ischemia, but a loss of these cells within hours of implantation could significantly diminish their long-term effect. We hypothesized that early coupling between BM-MSC and ischemic cardiomyocytes [...] Read more.
Bone marrow-derived mesenchymal stem cells (BM-MSC) are reported to induce beneficial effects in the heart following ischemia, but a loss of these cells within hours of implantation could significantly diminish their long-term effect. We hypothesized that early coupling between BM-MSC and ischemic cardiomyocytes through gap junctions (GJ) may play an important role in stem cell survival and retention in the acute phase of myocardial ischemia. To determine the effect of GJ inhibition on murine BM-MSC in vivo, we induced ischemia in mice using 90 min left anterior descending coronary artery (LAD) occlusion followed by BM-MSC implantation and reperfusion. The inhibition of GJ coupling prior to BM-MSC implantation led to early improvement in cardiac function compared to mice in which GJ coupling was not inhibited. Our results with in vitro studies also demonstrated increased survival in BM-MSCs subjected to hypoxia after inhibition of GJ. While functional GJ are critical for the long-term integration of stem cells within the myocardium, early GJ communication may represent a novel paradigm whereby ischemic cardiomyocytes induce a “bystander effect” when coupled to newly transplanted BM-MSC and thus impair cell retention and survival. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell 2.0: Greater Opportunities for Applications in Human Diseases)
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10 pages, 5971 KiB  
Communication
The Oncogenic Theory of Preeclampsia: Is Amniotic Mesenchymal Stem Cells-Derived PLAC1 Involved?
by Massimo Conese, Ottavio Napolitano, Onofrio Laselva, Sante Di Gioia, Luigi Nappi, Luigia Trabace and Maria Matteo
Int. J. Mol. Sci. 2023, 24(4), 3612; https://doi.org/10.3390/ijms24043612 - 10 Feb 2023
Cited by 1 | Viewed by 1165
Abstract
The pathomechanisms of preeclampsia (PE), a complication of late pregnancy characterized by hypertension and proteinuria, and due to improper placentation, are not well known. Mesenchymal stem cells derived from the amniotic membrane (AMSCs) may play a role in PE pathogenesis as placental homeostasis [...] Read more.
The pathomechanisms of preeclampsia (PE), a complication of late pregnancy characterized by hypertension and proteinuria, and due to improper placentation, are not well known. Mesenchymal stem cells derived from the amniotic membrane (AMSCs) may play a role in PE pathogenesis as placental homeostasis regulators. PLACenta-specific protein 1 (PLAC1) is a transmembrane antigen involved in trophoblast proliferation that is found to be associated with cancer progression. We studied PLAC1 in human AMSCs obtained from control subjects (n = 4) and PE patients (n = 7), measuring the levels of mRNA expression (RT-PCR) and secreted protein (ELISA on conditioned medium). Lower levels of PLAC1 mRNA expression were observed in PE AMSCs as compared with Caco2 cells (positive controls), but not in non-PE AMSCs. PLAC1 antigen was detectable in conditioned medium obtained from PE AMSCs, whereas it was undetectable in that obtained from non-PE AMSCs. Our data suggest that abnormal shedding of PLAC1 from AMSC plasma membranes, likely by metalloproteinases, may contribute to trophoblast proliferation, supporting its role in the oncogenic theory of PE. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell 2.0: Greater Opportunities for Applications in Human Diseases)
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13 pages, 3042 KiB  
Article
Intraperitoneally Delivered Umbilical Cord Lining Mesenchymal Stromal Cells Improve Survival and Kidney Function in Murine Lupus via Myeloid Pathway Targeting
by Alvin Wen Choong Chua, Dianyang Guo, Jia Chi Tan, Frances Ting Wei Lim, Chee Tian Ong, Jeyakumar Masilamani, Tony Kiat Hon Lim, William Ying Khee Hwang, Ivor Jiun Lim, Jinmiao Chen, Toan Thang Phan and Xiubo Fan
Int. J. Mol. Sci. 2023, 24(1), 365; https://doi.org/10.3390/ijms24010365 - 26 Dec 2022
Cited by 1 | Viewed by 1835
Abstract
To determine the therapeutic efficacy of human umbilical cord lining mesenchymal stromal cells (CL-MSCs) (US Patent number 9,737,568) in lupus-prone MRL/lpr (Faslpr) mice and elucidate its working mechanisms. A total of 4 doses of (20–25) × 106 cells/kg of CL-MSCs [...] Read more.
To determine the therapeutic efficacy of human umbilical cord lining mesenchymal stromal cells (CL-MSCs) (US Patent number 9,737,568) in lupus-prone MRL/lpr (Faslpr) mice and elucidate its working mechanisms. A total of 4 doses of (20–25) × 106 cells/kg of CL-MSCs was given to 16-week-old female Faslpr mice by intraperitoneal injection. Three subsequent doses were given on 17 weeks, 18 weeks, and 22 weeks, respectively. Six-week-old Faslpr mice were used as disease pre-onset controls. Mice were monitored for 10 weeks. Mouse kidney function was evaluated by examining complement component 3 (C3) deposition, urinary albumin-to-creatinine ratio (ACR), and lupus nephritis (LN) activity and chronicity. Working mechanisms were elucidated by flow cytometry, Luminex/ELISA (detection of anti-dsDNA and isotype antibodies), and RNA sequencing. CL-MSCs improved mice survival and kidney function by reducing LN activity and chronicity and lymphocyte infiltration over 10 weeks. CL-MSCs also reduced urinary ACR, renal complement C3 deposition, anti-dsDNA, and isotype antibodies that include IgA, IgG1, IgG2a, IgG2b, and IgM. Immune and cytokine profiling demonstrated that CL-MSCs dampened inflammation by suppressing splenic neutrophils and monocytes/macrophages, reducing plasma IL-6, IL-12, and CXCL1 and stabilizing plasma interferon-γ and TNF-α. RNA sequencing further showed that CL-MSCs mediated immunomodulation via concerted action of pro-proinflammatory cytokine-induced chemokines and production of nitric oxide in macrophages. CL-MSCs may provide a novel myeloid (neutrophils and monocytes/macrophages)-targeting therapy for SLE. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell 2.0: Greater Opportunities for Applications in Human Diseases)
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Review

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21 pages, 1683 KiB  
Review
Potential Role for Stem Cell Regenerative Therapy as a Treatment for Degenerative Disc Disease and Low Back Pain: A Systematic Review
by Khadija H. Soufi, Jose A. Castillo, Freddie Y. Rogdriguez, Charles J. DeMesa and Julius O. Ebinu
Int. J. Mol. Sci. 2023, 24(10), 8893; https://doi.org/10.3390/ijms24108893 - 17 May 2023
Cited by 7 | Viewed by 2676
Abstract
Back pain is the single leading cause of disability worldwide. Despite the prevalence and morbidity of lower back pain, we still lack a gold-standard treatment that restores the physiological function of degenerated intervertebral discs. Recently, stem cells have emerged as a promising strategy [...] Read more.
Back pain is the single leading cause of disability worldwide. Despite the prevalence and morbidity of lower back pain, we still lack a gold-standard treatment that restores the physiological function of degenerated intervertebral discs. Recently, stem cells have emerged as a promising strategy for regenerative therapy for degenerative disc disease. In this study, we review the etiology, pathogenesis, and developing treatment strategies for disc degeneration in low back pain with a focus on regenerative stem cell therapies. A systematic search of PubMed/MEDLINE/Embase/Clinical Trials.gov databases was conducted for all human subject abstracts or studies. There was a total of 10 abstracts and 11 clinical studies (1 RCT) that met the inclusion criteria. The molecular mechanism, approach, and progress of the different stem cell strategies in all studies are discussed, including allogenic bone marrow, allogenic discogenic cells, autologous bone marrow, adipose mesenchymal stem cells (MSCs), human umbilical cord MSC, adult juvenile chondrocytes, autologous disc derived chondrocytes, and withdrawn studies. Clinical success with animal model studies is promising; however, the clinical outcomes of stem cell regenerative therapy remain poorly understood. In this systematic review, we found no evidence to support its use in humans. Further studies on efficacy, safety, and optimal patient selection will establish whether this becomes a viable, non-invasive therapeutic option for back pain. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell 2.0: Greater Opportunities for Applications in Human Diseases)
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11 pages, 645 KiB  
Review
Molecular Mechanisms Responsible for Mesenchymal Stem Cell-Based Modulation of Obstructive Sleep Apnea
by Marija Zdravkovic, Carl Randall Harrell, Vladimir Jakovljevic, Valentin Djonov and Vladislav Volarevic
Int. J. Mol. Sci. 2023, 24(4), 3708; https://doi.org/10.3390/ijms24043708 - 13 Feb 2023
Viewed by 1563
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells that reside in almost all postnatal tissues where, due to the potent regenerative, pro-angiogenic and immunomodulatory properties, regulate tissue homeostasis. Obstructive sleep apnea (OSA) induces oxidative stress, inflammation and ischemia which recruit MSCs from their [...] Read more.
Mesenchymal stem cells (MSCs) are adult stem cells that reside in almost all postnatal tissues where, due to the potent regenerative, pro-angiogenic and immunomodulatory properties, regulate tissue homeostasis. Obstructive sleep apnea (OSA) induces oxidative stress, inflammation and ischemia which recruit MSCs from their niches in inflamed and injured tissues. Through the activity of MSC-sourced anti-inflammatory and pro-angiogenic factors, MSCs reduce hypoxia, suppress inflammation, prevent fibrosis and enhance regeneration of damaged cells in OSA-injured tissues. The results obtained in large number of animal studies demonstrated therapeutic efficacy of MSCs in the attenuation of OSA-induced tissue injury and inflammation. Herewith, in this review article, we emphasized molecular mechanisms which are involved in MSC-based neo-vascularization and immunoregulation and we summarized current knowledge about MSC-dependent modulation of OSA-related pathologies. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell 2.0: Greater Opportunities for Applications in Human Diseases)
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24 pages, 380 KiB  
Review
Serum-Free Cultures: Could They Be a Future Direction to Improve Neuronal Differentiation of Mesenchymal Stromal Cells?
by Giovanni Schepici, Agnese Gugliandolo and Emanuela Mazzon
Int. J. Mol. Sci. 2022, 23(12), 6391; https://doi.org/10.3390/ijms23126391 - 07 Jun 2022
Cited by 5 | Viewed by 1993
Abstract
Mesenchymal stem/stromal cells (MSCs) are undifferentiated cells with multilinear potential, known for their immunomodulatory and regenerative properties. Although the scientific community is working to improve their application, concerns limit their use to repair tissues following neurological damage. One of these obstacles is represented [...] Read more.
Mesenchymal stem/stromal cells (MSCs) are undifferentiated cells with multilinear potential, known for their immunomodulatory and regenerative properties. Although the scientific community is working to improve their application, concerns limit their use to repair tissues following neurological damage. One of these obstacles is represented by the use of culture media supplemented with fetal bovine serum (FBS), which, due to its xenogenic nature and the risk of contamination, has increased scientific, ethical and safety problems. Therefore, the use of serum-free media could improve MSC culture methods, avoiding infectious and immunogenic transmission problems as well as MSC bioprocesses, without the use of animal components. The purpose of our review is to provide an overview of experimental studies that demonstrate that serum-free cultures, along with the supplementation of growth factors or chemicals, can lead to a more defined and controlled environment, enhancing the proliferation and neuronal differentiation of MSCs. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell 2.0: Greater Opportunities for Applications in Human Diseases)
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