Therapeutic Properties of Mesenchymal Stromal/Stem Cells: The Need of Cell Priming for Cell-Free Therapies in Regenerative Medicine

Mesenchymal stromal/stem cells (MSCs) are multipotent adult stem cells that support homeostasis during tissue regeneration. In the last decade, cell therapies based on the use of MSCs have emerged as a promising strategy in the field of regenerative medicine. Although these cells possess robust therapeutic properties that can be applied in the treatment of different diseases, variables in preclinical and clinical trials lead to inconsistent outcomes. MSC therapeutic effects result from the secretion of bioactive molecules affected by either local microenvironment or MSC culture conditions. Hence, MSC paracrine action is currently being explored in several clinical settings either using a conditioned medium (CM) or MSC-derived exosomes (EXOs), where these products modulate tissue responses in different types of injuries. In this scenario, MSC paracrine mechanisms provide a promising framework for enhancing MSC therapeutic benefits, where the composition of secretome can be modulated by priming of the MSCs. In this review, we examine the literature on the priming of MSCs as a tool to enhance their therapeutic properties applicable to the main processes involved in tissue regeneration, including the reduction of fibrosis, the immunomodulation, the stimulation of angiogenesis, and the stimulation of resident progenitor cells, thereby providing new insights for the therapeutic use of MSCs-derived products.

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Wharton’s Jelly Derived Mesenchymal Stem Cells: Future of Regenerative Medicine? Recent Findings and Clinical Significance

BioMed Research International ◽

10.1155/2015/430847 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 82

Author(s):

Ilona Kalaszczynska ◽

Katarzyna Ferdyn

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Regenerative Medicine ◽

Adult Stem Cells ◽

Wharton’S Jelly ◽

Therapeutic Effects ◽

Ethical Concerns ◽

Wharton's Jelly ◽

Privileged Status ◽

Therapeutic Properties

Around 5 million annual births in EU and 131 million worldwide give a unique opportunity to collect lifesaving Wharton’s jelly derived mesenchymal stem cells (WJ-MSC). Evidences that these cells possess therapeutic properties are constantly accumulating. Collection of WJ-MSC is done at the time of delivery and it is easy and devoid of side effects associated with collection of adult stem cells from bone marrow or adipose tissue. Likewise, their rate of proliferation, immune privileged status, lack of ethical concerns, nontumorigenic properties make them ideal for both autologous and allogeneic use in regenerative medicine applications. This review provides an outline of the recent findings related to WJ-MSC therapeutic effects and possible advantage they possess over MSC from other sources. Results of first clinical trials conducted to treat immune disorders are highlighted.

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Mesenchymal Stromal/Stem Cells in Regenerative Medicine and Tissue Engineering

Stem Cells International ◽

10.1155/2018/8031718 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 96

Author(s):

Ross E. B. Fitzsimmons ◽

Matthew S. Mazurek ◽

Agnes Soos ◽

Craig A. Simmons

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Regenerative Medicine ◽

Ex Vivo ◽

Therapeutic Effects ◽

Wide Range ◽

History Of ◽

Initial Discovery ◽

Stromal Stem Cells

As a result of over five decades of investigation, mesenchymal stromal/stem cells (MSCs) have emerged as a versatile and frequently utilized cell source in the fields of regenerative medicine and tissue engineering. In this review, we summarize the history of MSC research from the initial discovery of their multipotency to the more recent recognition of their perivascular identity in vivo and their extraordinary capacity for immunomodulation and angiogenic signaling. As well, we discuss long-standing questions regarding their developmental origins and their capacity for differentiation toward a range of cell lineages. We also highlight important considerations and potential risks involved with their isolation, ex vivo expansion, and clinical use. Overall, this review aims to serve as an overview of the breadth of research that has demonstrated the utility of MSCs in a wide range of clinical contexts and continues to unravel the mechanisms by which these cells exert their therapeutic effects.

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Changes in the Transcriptome Profiles of Human Amnion-Derived Mesenchymal Stromal/Stem Cells Induced by Three-Dimensional Culture: A Potential Priming Strategy to Improve Their Properties

International Journal of Molecular Sciences ◽

10.3390/ijms23020863 ◽

2022 ◽

Vol 23 (2) ◽

pp. 863

Author(s):

Alessia Gallo ◽

Nicola Cuscino ◽

Flavia Contino ◽

Matteo Bulati ◽

Mariangela Pampalone ◽

...

Keyword(s):

Stem Cells ◽

Three Dimensional ◽

3D Culture ◽

Therapeutic Effects ◽

Rna Seq ◽

Human Amnion ◽

Cell Based Therapy ◽

Therapeutic Properties ◽

Stromal Stem Cells

Mesenchymal stromal/stem cells (MSCs) are believed to function in vivo as a homeostatic tool that shows therapeutic properties for tissue repair/regeneration. Conventionally, these cells are expanded in two-dimensional (2D) cultures, and, in that case, MSCs undergo genotypic/phenotypic changes resulting in a loss of their therapeutic capabilities. Moreover, several clinical trials using MSCs have shown controversial results with moderate/insufficient therapeutic responses. Different priming methods were tested to improve MSC effects, and three-dimensional (3D) culturing techniques were also examined. MSC spheroids display increased therapeutic properties, and, in this context, it is crucial to understand molecular changes underlying spheroid generation. To address these limitations, we performed RNA-seq on human amnion-derived MSCs (hAMSCs) cultured in both 2D and 3D conditions and examined the transcriptome changes associated with hAMSC spheroid formation. We found a large number of 3D culture-sensitive genes and identified selected genes related to 3D hAMSC therapeutic effects. In particular, we observed that these genes can regulate proliferation/differentiation, as well as immunomodulatory and angiogenic processes. We validated RNA-seq results by qRT-PCR and methylome analysis and investigation of secreted factors. Overall, our results showed that hAMSC spheroid culture represents a promising approach to cell-based therapy that could significantly impact hAMSC application in the field of regenerative medicine.

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Towards a Comprehensive Understanding of UA-ADRCs (Uncultured, Autologous, Fresh, Unmodified, Adipose Derived Regenerative Cells, Isolated at Point of Care) in Regenerative Medicine

Cells ◽

10.3390/cells9051097 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1097 ◽

Cited By ~ 2

Author(s):

Eckhard U. Alt ◽

Glenn Winnier ◽

Alexander Haenel ◽

Ralf Rothoerl ◽

Oender Solakoglu ◽

...

Keyword(s):

Stem Cells ◽

Adipose Tissue ◽

Regenerative Medicine ◽

Tissue Regeneration ◽

Adult Stem Cells ◽

Point Of Care ◽

Initial Mixture ◽

Physiological Capacity ◽

Regenerative Cells ◽

Regenerate Tissue

It has become practically impossible to survey the literature on cells derived from adipose tissue for regenerative medicine. The aim of this paper is to provide a comprehensive and translational understanding of the potential of UA-ADRCs (uncultured, unmodified, fresh, autologous adipose derived regenerative cells isolated at the point of care) and its application in regenerative medicine. We provide profound basic and clinical evidence demonstrating that tissue regeneration with UA-ADRCs is safe and effective. ADRCs are neither ‘fat stem cells’ nor could they exclusively be isolated from adipose tissue. ADRCs contain the same adult stem cells ubiquitously present in the walls of blood vessels that are able to differentiate into cells of all three germ layers. Of note, the specific isolation procedure used has a significant impact on the number and viability of cells and hence on safety and efficacy of UA-ADRCs. Furthermore, there is no need to specifically isolate and separate stem cells from the initial mixture of progenitor and stem cells found in ADRCs. Most importantly, UA-ADRCs have the physiological capacity to adequately regenerate tissue without need for more than minimally manipulating, stimulating and/or (genetically) reprogramming the cells for a broad range of clinical applications. Tissue regeneration with UA-ADRCs fulfills the criteria of homologous use as defined by the regulatory authorities.

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Adipose-Derived Stem Cells for Future Regenerative System Medicine

The Indonesian Biomedical Journal ◽

10.18585/inabj.v4i2.164 ◽

2012 ◽

Vol 4 (2) ◽

pp. 59

Author(s):

Yani Lina ◽

Andi Wijaya

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Adipose Tissue ◽

Regenerative Medicine ◽

Adult Stem Cells ◽

Stromal Vascular Fraction ◽

Human Adipose Tissue ◽

Lytic Enzymes ◽

Stromal Stem Cells

BACKGROUND: The potential use of stem cell-based therapies for repair and regeneration of various tissues and organs offers a paradigm shift that may provide alternative therapeutic solutions for a number of disease. Despite the advances, the availability of stem cells remaining a challenge for both scientist and clinicians in pursuing regenerative medicine. CONTENT: Subcutaneous human adipose tissue is an abundant and accessible cell source for applications in tissue engineering and regenerative medicine. Routinely, the adipose issue is digested with collagenase or related lytic enzymes to release a heterogeneous population for stromal vascular fraction (SVF) cells. The SVF cells can be used directly or can be cultured in plastic ware for selection and expansion of an adherent population known as adipose-derived stromal/stem cells (ASCs). Their potential in the ability to differentiate into adipogenic, osteogenic, chondrogenic and other mesenchymal lineages, as well in their other clinically useful properties, includes stimulation of angiogenesis and suppression of inflammation.SUMMARY: Adipose tissue is now recognized as an accessible, abundant and reliable site for the isolation of adult stem cels suitable for the application of tissue engineering and regenerative medicine applications. The past decade has witnessed an explosion of preclinical data relating to the isolation, characterization, cryopreservation, differentiation, and transplantation of freshly isolated stromal vascular fraction cells and adherent, culture-expanded, adipose-derived stromal/stem cells in vitro and in animal models.KEYWORDS: adipose tissue, adult stem cells, regenerative medicine, mesenchymal stem cells

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Importance of Stem Cell Migration and Angiogenesis Study for Regenerative Cell-based Therapy: A Review

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200127145923 ◽

2020 ◽

Vol 15 (3) ◽

pp. 284-299

Author(s):

Nur S. Aziz ◽

Norhayati Yusop ◽

Azlina Ahmad

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Regenerative Medicine ◽

Tissue Regeneration ◽

Adult Stem Cells ◽

Research Work ◽

Regeneration Process ◽

Future Research ◽

Species Variation ◽

Cell Based Therapy

Stem cells play an essential role in maintaining homeostasis, as well as participating in new tissue regeneration. Over the past 20 years, a great deal of effort has been made to investigate the behaviour of stem cells to enable their potential use in regenerative medicine. However, a variety of biological characteristics are known to exist among the different types of stem cells due to variations in the methodological approach, formulation of cell culture medium, isolation protocol and cellular niches, as well as species variation. In recent years, cell-based therapy has emerged as one of the advanced techniques applied in both medical and clinical settings. Cell therapies aim to treat and repair the injury sites and replace the loss of tissues by stimulating the repair and regeneration process. In order to enable the use of stem cells in regenerative therapies, further characterisation of cell behaviour, in terms of their proliferation and differentiation capacity, mainly during the quiescent and inductive state is regarded as highly necessary. The central focus of regenerative medicine revolves around the use of human cells, including adult stem cells and induced pluripotent stem cells for cell-based therapy. The purpose of this review was to examine the existing body of literature on stem cell research conducted on cellular angiogenesis and migration, to investigate the validity of different strategies and variations of the cell type used. The information gathered within this review may then be shared with fellow researchers to assist in future research work, engaging in stem cell homing for cell-based therapy to enhance wound healing and tissue regeneration process.

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Regenerative Potential of the Product “CardioCell” Derived from the Wharton’s Jelly Mesenchymal Stem Cells for Treating Hindlimb Ischemia

International Journal of Molecular Sciences ◽

10.3390/ijms20184632 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4632 ◽

Cited By ~ 3

Author(s):

Musiał-Wysocka ◽

Kot ◽

Sułkowski ◽

Majka

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Regenerative Medicine ◽

Wharton’S Jelly ◽

Great Promise ◽

Therapeutic Effects ◽

Hindlimb Ischemia ◽

Wharton's Jelly ◽

Cell Based Therapy ◽

Therapeutic Benefits

In recent years, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic modality in regenerative medicine. They hold great promise for treating civilization-wide diseases, including cardiovascular diseases, such as acute myocardial infarction and critical limb ischemia. MSCs isolated from Wharton’s jelly (WJ-MSCs) may be utilized in both cell-based therapy and vascular graft engineering to restore vascular function, thereby providing therapeutic benefits for patients. The efficacy of WJ-MSCs lies in their multipotent differentiation ability toward vascular smooth muscle cells, endothelial cells and other cell types, as well as their capacity to secrete various trophic factors, which are potent in promoting angiogenesis, inhibiting apoptosis and modulating immunoreaction. Ischemic limb disease is caused by insufficient nutrient and oxygen supplies resulting from damaged peripheral arteries. The lack of nutrients and oxygen causes severe tissue damage in the limb, thereby resulting in severe morbidities and mortality. The therapeutic effects of the conventional treatments are still not sufficient. Cell transplantations in small animal model (mice) are vital for deciphering the mechanisms of MSCs’ action in muscle regeneration. The stimulation of angiogenesis is a promising strategy for the treatment of ischemic limbs, restoring blood supply for the ischemic region. In the present study, we focus on the therapeutic properties of the human WJ-MSCs derived product, Cardio. We investigated the role of CardioCell in promoting angiogenesis and relieving hindlimb ischemia. Our results confirm the healing effect of CardioCell and strongly support the use of the WJ-MSCs in regenerative medicine.

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Effects of Extracellular Vesicles Derived from Mesenchymal Stem/Stromal Cells on Liver Diseases

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190308123714 ◽

2019 ◽

Vol 14 (5) ◽

pp. 442-452 ◽

Cited By ~ 1

Author(s):

Wenjie Zheng ◽

Yumin Yang ◽

Russel Clive Sequeira ◽

Colin E. Bishop ◽

Anthony Atala ◽

...

Keyword(s):

Regenerative Medicine ◽

Extracellular Vesicles ◽

Stromal Cells ◽

Liver Diseases ◽

Therapeutic Potential ◽

Mechanisms Of Action ◽

Therapeutic Effects ◽

Chronic Liver Injury ◽

Mediated Effects ◽

Therapeutic Benefits

Therapeutic effects of Mesenchymal Stem/Stromal Cells (MSCs) transplantation have been observed in various disease models. However, it is thought that MSCs-mediated effects largely depend on the paracrine manner of secreting cytokines, growth factors, and Extracellular Vesicles (EVs). Similarly, MSCs-derived EVs also showed therapeutic benefits in various liver diseases through alleviating fibrosis, improving regeneration of hepatocytes, and regulating immune activity. This review provides an overview of the MSCs, their EVs, and their therapeutic potential in treating various liver diseases including liver fibrosis, acute and chronic liver injury, and Hepatocellular Carcinoma (HCC). More specifically, the mechanisms by which MSC-EVs induce therapeutic benefits in liver diseases will be covered. In addition, comparisons between MSCs and their EVs were also evaluated as regenerative medicine against liver diseases. While the mechanisms of action and clinical efficacy must continue to be evaluated and verified, MSCs-derived EVs currently show tremendous potential and promise as a regenerative medicine treatment for liver disease in the future.

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Extracellular Vesicles of Mesenchymal Stem Cells: Therapeutic Properties Discovered with Extraordinary SuccessOK

Biomedicines ◽

10.3390/biomedicines9060667 ◽

2021 ◽

Vol 9 (6) ◽

pp. 667

Author(s):

Gabriella Racchetti ◽

Jacopo Meldolesi

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Immune Responses ◽

Extracellular Vesicles ◽

Immune Regulation ◽

Great Increase ◽

The Body ◽

Cell Aging ◽

Therapeutic Effects ◽

Therapeutic Properties

Mesenchymal stem cells (MSCs), the cells distributed in the stromas of the body, are known for various properties including replication, the potential of various differentiations, the immune-related processes including inflammation. About two decades ago, these cells were shown to play relevant roles in the therapy of numerous diseases, dependent on their immune regulation and their release of cytokines and growth factors, with ensuing activation of favorable enzymes and processes. Such discovery induced great increase of their investigation. Soon thereafter, however, it became clear that therapeutic actions of MSCs are risky, accompanied by serious drawbacks and defects. MSC therapy has been therefore reduced to a few diseases, replaced for the others by their extracellular vesicles, the MSC-EVs. The latter vesicles recapitulate most therapeutic actions of MSCs, with equal or even better efficacies and without the serious drawbacks of the parent cells. In addition, MSC-EVs are characterized by many advantages, among which are their heterogeneities dependent on the stromas of origin, the alleviation of cell aging, the regulation of immune responses and inflammation. Here we illustrate the MSC-EV therapeutic effects, largely mediated by specific miRNAs, covering various diseases and pathological processes occurring in the bones, heart and vessels, kidney, and brain. MSC-EVs operate also on the development of cancers and on COVID-19, where they alleviate the organ lesions induced by the virus. Therapy by MSC-EVs can be improved by combination of their innate potential to engineering processes inducing precise targeting and transfer of drugs. The unique properties of MSC-EVs explain their intense studies, carried out with extraordinary success. Although not yet developed to clinical practice, the perspectives for proximal future are encouraging.

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Stem Cell-Engineered Nanovesicles Exert Proangiogenic and Neuroprotective Effects

Materials ◽

10.3390/ma14051078 ◽

2021 ◽

Vol 14 (5) ◽

pp. 1078

Author(s):

Han Young Kim ◽

Suk Ho Bhang

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Mesenchymal Stem Cells ◽

Tissue Regeneration ◽

Therapeutic Agent ◽

Therapeutic Effects ◽

Hydrodynamic Size ◽

Regeneration Strategy ◽

Neuroprotective Effects ◽

The Poor

As a tissue regeneration strategy, the utilization of mesenchymal stem cells (MSCs) has drawn considerable attention. Comprehensive research using MSCs has led to significant preclinical or clinical outcomes; however, improving the survival rate, engraftment efficacy, and immunogenicity of implanted MSCs remains challenging. Although MSC-derived exosomes were recently introduced and reported to have great potential to replace conventional MSC-based therapeutics, the poor production yield and heterogeneity of exosomes are critical hurdles for their further applications. Herein, we report the fabrication of exosome-mimetic MSC-engineered nanovesicles (MSC-NVs) by subjecting cells to serial extrusion through filters. The fabricated MSC-NVs exhibit a hydrodynamic size of ~120 nm, which is considerably smaller than the size of MSCs (~30 μm). MSC-NVs contain both MSC markers and exosome markers. Importantly, various therapeutic growth factors originating from parent MSCs are encapsulated in the MSC-NVs. The MSC-NVs exerted various therapeutic effects comparable to those of MSCs. They also significantly induced the angiogenesis of endothelial cells and showed neuroprotective effects in damaged neuronal cells. The results collectively demonstrate that the fabricated MSC-NVs can serve as a nanosized therapeutic agent for tissue regeneration.

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