|Year : 2019 | Volume
| Issue : 3 | Page : 93-101
Human umbilical cord-derived mesenchymal stem cells: Current trends and future perspectives
Diego Rossetti M.D. 1, Silvia Di Angelo Antonio2, David Lukanović3, Tina Kunic3, Camilla Certelli4, Carmine Vascone5, Zaki Sleiman6
1 Unit of Gynecology and Obstetrics, Desenzano del Garda Hospital, Section of Gavardo, Gavardo, Brescia, Italy
2 Department of Biomedicine and Prevention, Section of Gynecology and Obstetrics, University of Rome Tor Vergata, Rome, Italy
3 Department of Obstetrics and Gynecology, University Medical Center Ljubljana, Ljubljana, Slovenia
4 Gynecologic Oncology Unit, Department of Experimental Clinical Oncology, "Regina Elena" National Cancer Institute, Rome, Italy
5 Pineta Grande Hospital, Castel Volturno, Caserta, Italy
6 Surgical Research Laboratory, Medical School, Saint Joseph University, Damas Street; Department of Obstetrics and Gynaecology, Lebanese American University, Beirut, Lebanon
|Date of Submission||09-Jan-2019|
|Date of Decision||05-Apr-2019|
|Date of Acceptance||25-Apr-2019|
|Date of Web Publication||29-May-2019|
Unit of Gynecology and Obstetrics, Desenzano del Garda Hospital, Section of Gavardo, Gavardo, Brescia
Source of Support: None, Conflict of Interest: None
Among resources of mesenchymal stem cells, human umbilical cord appears to be a rising source capable of differentiating into all germ layers, reaching and repairing lesion areas, and promoting wound repair, and it has also the capacity to influence the immune response. Human umbilical cord-derived mesenchymal stem cells are considered to be an optimal resource compared with other mesenchymal stem cells sources because they require a noninvasive recovery. All these characteristics allow their use in heterogeneous applications. Human umbilical cord-derived mesenchymal stem cells can regenerate tissues, stimulate angiogenesis, modulate inflammatory pathway signals and recruit endogenous stem cell. Human umbilical cord-derived mesenchymal stem cells suppress mitogen-induced signals and modulate the activation and proliferation of several immune cells, modifying lymphocyte phenotypes activity. In culture, human umbilical cord-derived mesenchymal stem cellss show the capacity to create several tissues such as bone, cartilage, and fat. Human umbilical cord-derived mesenchymal stem cells can be isolated from the different compartments of umbilical cord and processed by using different techniques. Clinical applications of human umbilical cord-derived mesenchymal stem cells include graft-versus-host disease, autoimmune diseases such as Sjögren's syndrome and diabetes mellitus types 1 and 2, gynecological disorders like endometriosis. Recent studies have shown possible application on rheumatoid arthritis, osteoarthritis, and neuronal degenerative diseases. This review is focused on the resources, molecular profiles, propriety, in vitro characterizations, clinical applications and possible future usage of human umbilical cord-derived mesenchymal stem cells.
Keywords: Human umbilical cord stem cells, Immunomodulation, Cryopreservation, Stem therapy
|How to cite this article:|
Rossetti D, Di Angelo Antonio S, Lukanović D, Kunic T, Certelli C, Vascone C, Sleiman Z. Human umbilical cord-derived mesenchymal stem cells: Current trends and future perspectives. Asian Pac J Reprod 2019;8:93-101
|How to cite this URL:|
Rossetti D, Di Angelo Antonio S, Lukanović D, Kunic T, Certelli C, Vascone C, Sleiman Z. Human umbilical cord-derived mesenchymal stem cells: Current trends and future perspectives. Asian Pac J Reprod [serial online] 2019 [cited 2021 Dec 9];8:93-101. Available from: http://www.apjr.net/text.asp?2019/8/3/93/259166
| 1. Introduction|| |
Mesenchymal stem cells (MSCs) possess characteristics of multipotent cells. Considering stem cells and mesenchymal progenitors of cells, they can differentiate into several tissues. Stem cells are able to self-renew, and at the same time, by asymmetric cell division or after specific activation, to generate lineage progenitor cells or differentiated cells. MSCs can be found in different human tissues such as fat, umbilical cord (UC), skin, placenta, amniotic fluid, synovial membranes, muscle and fetal tissues,,,,. Due to their immunomodulatory properties and potential for tissue regeneration, they can be used therapeutically, especially for autoimmune and degenerative diseases.
UC, a fetal-placental unit component, is composed of vessels (two arteries and one vein) surrounded by a specific mesenchymal tissue named Wharton's jelly. Among UC components, there are MSCs that demonstrate similar characteristic to other MSC sources. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are an optimal resource compared with others, as MSCs require noninvasive recovery and they are a source of a good amount of MSCs. Moreover, they are not compounded by ethical problems and can be used for heterogeneous application,. For this reason, the aim of our systematic review is to discuss characteristics, the isolation methods and in vitro and in vivo studies and applications of UC-MSCs.
| 2. Materials and methods|| |
2.1. Search and screening of literature
We searched the following electronic bibliographic databases: MEDLINE, EMBASE, PsycINFO, Global Health, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), Health Technology Assessment Database, and Web of Science (science and social science citation index). The search strategy included only terms relating to or describing the intervention, adapted for use with other bibliographic databases in combination with database-specific filters for controlled trials (where these are available): “human umbilical cord stem cells”; “isolation of cord stem cells”; “immunomodulation of human umbilical cord stem cells”; “tissue regenerative properties of human umbilical cord stem cells”; and “human umbilical cord stem cells therapies”. The search included articles in English language from the inception of the abovementioned databases to 1 April 2019.
2.2. Data extraction
Titles and/or abstracts of studies retrieved using the search strategy and those from additional sources were screened independently by two review authors (D.R., C.C.) to identify studies that potentially meet the inclusion criteria outlined above. The full texts of these potentially eligible studies were retrieved and independently assessed for eligibility by two review team members (D.L., C.V.). Any disagreement between them over the eligibility of particular studies was resolved through discussion with a third (external) collaborator. A standardized, pre-piloted form was used to extract data from the included studies for assessment and evidence synthesis. Two review authors extracted data independently (S.D.A.A., T.K.), discrepancies were identified and resolved through discussion (with a third external collaborator where necessary). Missing data were requested from study authors, when required.
2.3. Data synthesis
Considering the range of different outcomes measured across the studies and the very limited number of trials, we provided a narrative synthesis of the findings from the included articles. In particular, we divided these results into subchapters: “history and characteristic of MSCs and UC-MSCs”, “isolation and storage of UC-MSCs”, “in vitro and animal study” and “human protocols”.
| 3. Results|| |
We identified 13 809 articles, using the search strategy as detailed in the “Materials and methods” section, and 875 additional sources. After duplicates removed, we screened the remaining 234 articles: afterwards, we excluded 127 articles (89 were not published in English, 38 did not report detailed information about the topic). We retrieved and evaluate the remaining 107 articles, and further excluded 56 of them since they did not report detailed information about the topic. Data extracted from the remaining 51 studies are synthetized in the next sections. The full search, screening, and selection of the articles was summarized in the flow diagram of preferred reporting items for systematic reviews and meta-analyses [Figure 1].
|Figure 1: Flow diagram of full search, screening and selection of articles.|
Click here to view
3.1. History and characteristic of MSCs and UC-MSCs
Since Conheim's first discovery in 1867, concerning the presence of non-hematopoietic stem cells in bone marrow, numerous studies have been published. The stem cells, first observed in bone marrow as plastic-adherent fibroblastic cells capable of creating colonies in vitro, were named MSCs. They demonstrated the ability to differentiate into a variety of mesodermal cell types in vitro, such as osteoblasts, chondrocytes, adipocytes, and myoblasts,,. MSCs can be found in several human tissues such as fat sources, dental pulp, tendon, UC, skin, placenta, amniotic fluid, synovial membranes, muscle and fetal tissues,,,,,,. The UC, similar to bone marrow, contains a considerable amount of MSCs. The UC-MSCs are easily collected at the time of birth following either normal vaginal delivery or cesarean section and can be used in the heterogeneous application. Their cost is yet considerably less expensive when compared to other invasive procedures such as bone marrow aspiration. Several studies demonstrated that UC-MSCs have a similar surface phenotype, differentiation capability, and immune properties compared to bone marrow and adipose MSCs. UC-MSCs, in particular, have more in common with fetal MSCs in terms of their in vitro expansion potential. UC-MSCs have the ability to generate multipotent in vitro and adherent cells with osteogenic and chondrogenic potential. There are two different morphological phenotypes: flattened fibroblasts (majority) and spindle-shaped fibroblasts (minority) and they exhibit similar cell surface markers. MSCs are negative for CD34, CD26, CD31, CD73, CD90, CD105, CD44, and human lymphocyte antigen (HLA)-DR. They are positive for mesenchymal progenitor markers SH2, SH3, and SH4; adherent molecules CD29, CD44 and HLA-A, B, C. However, a difference in CD90 expression was observed. Both morphological phenotypes of MSCs have shown the ability to differentiate into osteogenic and chondrogenic lines, but the flattened type has shown less capability in terms of differentiation and adipogenesis. This characteristic justifies the lesser sensitivity of UC-MSCs compared with bone marrow MSCs in generating adipogenic tissues,. Comparative proteomic analysis of bone marrow, placenta and adipose tissue derived from MSCs showed that 90 proteins were expressed differently according to their functional tissue orientation towards chondrogenic, adipogenic or osteogenic differentiation, such as apoptosis, oxidative stress and peroxiredoxin activity, stathmin, transgelin, tropomyosin, and heat shock protein 27. Placenta-derived MSCs, similar to UC-MSCs, have a lower potential for undergoing adipogenesis but have a higher potential for undergoing osteogenesis compared to other MSCs. Due to the presence of highly up-regulated apoptosis, oxidative stress and peroxiredoxin activity proteins, fetal-MSCs seem to be potential in the treatment of cellular ischemic disease caused by hypoxic conditions. UC-MSCs are easily found, manageable and expandable in vitro; they can be used in the heterogeneous application, cryogenically stored and reanimated. MSCs must be managed in compliance with good medical practice. Therefore, cells must be tested in accordance with the high standards of sterility protocols, quality control, storage and documentation.
3.2. Isolation and storage of UC-MSC
In order to carry out UC-MSC isolation and storage, informed consent should be obtained from each donor-mother prior to delivery.
Afterwards, collection is obtained from the UC or explanted from several body compartments. Collected tissue should be then stored in 0.9% saline solution, handled and processed in a sterilized container within 12-24 h after delivery, using phosphate buffered saline in order to remove blood residues. Among the various techniques used to isolate UC-MSCs, we address hereby the most commonly practiced.
3.3. Explant method
The first step is to remove blood vessels from the UC and cut them into small parts. Later on, the UC fragments are put into a culture-treated dish where they are attached to the bottom, using a medium replaced every 3.7 days for 2-4 weeks until a high level of fibroblast concentration is obtained. Following this, the UC fragments are detached through a trypsin solution and filtered. As one can imagine, the main limit of this technique is the low rate of retrieved cells due to the gross tissue fragments within the medium.
3.4. Enzymatic digestion method
In this method, it is important to remove the blood vessels, cut the UC into small parts of about 4 cm in well-lit conditions with a sterile blade, then mince and digest them with a specific enzyme solution at 37 °C. Among the different enzymes, the most used are collagenase and hyaluronidase, with or without trypsin. Subsequently, cells are divided into two parts: the first is frozen in liquid nitrogen; the second is cultured with standard conditions and specific culture media. For instance, it is possible to use the alpha minimum essential culture media supplemented with 2 mmol/L L-glutamine, 100 U penicillin /1 000 U streptomycin and 15% fetal bovine serum,. The culture medium is changed every 3-7 days for at least 2 weeks until a high level of fibroblast concentration is obtained. After culture, cells are divided into two parts as before: one frozen and the other used for immunophenotypic assays. Cells are counted by an automated cell counter system and the growth rate is calculated through doubling time evaluation. Flow cytometry analysis is usually arranged in the dark for 30 min at room temperature using specific antibodies such as CD105-PerCP-Cy5.5, CD31-phycoerythrin (PE), CD73-allophycocyanin, CD34-PE, PE-CD11b, CD90-fluorescein isothiocyanate, CD44-PE, CD19-PE, PE-CD117, CD146-PE and HLA-DR-PE.
3.5. In vitro and animal study
Among MSCs, UC-MSCs show remarkable plasticity, capable of differentiating in vitro into different lines of multipotent cells: adipocytes, osteoblasts, myogenic cells, neurons, and cardiomyocytes. They demonstrate a simultaneous immune-privilege due to the lack of HLA-DR and immune-modulatory properties. These characteristics have made UC-MSCs a new clinical tool in the exploration of new medical frontiers in several autoimmune and chronic inflammatory disorders and in the repair of injured tissue,,,,,. Several studies were carried out, both in vitro and in vivo, to demonstrate the capability of UC-MSCs in modulating the immune system, repopulating and regenerating damaged tissues as well as in producing immunomodulation and immunosuppression function, changing the pathological mechanism of some diseases.
UC-MSCs are candidate cells in the treatment of autoimmune diseases thanks to their immunomodulatory properties, for example, their ability to modify systemic lupus erythematosus disease by increasing the frequency of peripheral T-regulatory (Treg) cells and re-establishing the balance between lymphocytes T helper (Th)1-and Th2-related cytokines. Yang et al demonstrated that UC-MSCs co-cultured with peripheral blood mononuclear cells are capable of suppressing mitogen-induced peripheral blood mononuclear cell activation and proliferation, modifying T lymphocyte phenotypes in vitro and changing the cytokine secretion profile. They are capable of determining a shift into anti-inflammatory cytokine pattern. Polyethylene glycol 2, transforming growth factor-b, and interleukin (IL)-10 are also up-regulated, with a contemporarily significant down-regulation of the pro-inflammatory cytokine pattern as interferon-c. UC-MSCs can influence natural killer cell-mediated interferon-γ production. They suppress the causes of IL-12/IL-18 rise due to the phosphorylation of signal transducers and activators of transcription 4, nuclear factor-kB, T-bet activity and releasing of activin-A.
UC-MSCs also express nucleotide-binding oligomerization domain 2 capable of regulating the inflammatory intestinal background in adult animals, which is, as already known, linked with inflammatory bowel diseases such as Chron's disease. In vivo studies have shown how UC-MSCs administered in mice with colitis, thanks to the activation of nucleotide-binding oligomerization domain 2 with its ligand, muramyl dipeptide, increase anti-inflammatory responses, thus raising the production of IL-10 and other immune regulatory molecules such as forkhead box protein P3, transforming growth factor-β , arginase type II, C-C motif chemokine ligand 22, heme oxygenase-1, and tumor necrosis factor α stimulated gene 6, promoting the infiltration of Treg cells and reducing the production of inflammatory cytokines. In particular, UC-MSCs injected into the bloodstream of mice do not reach the inflamed bowel directly but form aggregates in the peritoneum where they produce immunoregulatory molecules, including tumor necrosis factor-stimulated gene-6, that reduce intestinal inflammation,. Diabetes mellitus is a chronic metabolic disease consisting of uncontrolled high levels of glucose in the blood. Diabetes mellitus type 1 affects young people with autoimmune destruction of pancreatic β -cells and is mainly in Th1 disease correlated with the synergic action of CD4+ and CD8+ cells on the β -cell destruction process. Moreover, Th17, with their interleukin and reduction in Treg concentration, may play a crucial role in triggering autoimmunity in the early stages of several autoimmune diseases, including diabetes mellitus type 1,,,. In a study by Montanucci et al, using an in vitro microencapsulated drug biohybrid UC-MSCs, they demonstrated the reduction of effector Th1 cells, the expansion of Treg cells which led to the rebalancing of the effector T cell/Treg ratio, up-regulation of indoleamine 2,3-dioxygenase 1, which is a master regulator of tolerance that mediates the differentiation in Treg. Nevertheless, no suppressive activity on Th17 cells was observed and the Th17 is insensitive to UC-MSCs immunomodulation. Similar evidence was found in another autoimmune disorder, Sjögren's syndrome, using the same technology of the biohybrid drug system. Sjögren's syndrome is a systemic autoimmune disorder characterized by chronic inflammation of exocrine glands. In Sjögren's syndrome models, microencapsulated UC-MSCs reduce T cell proliferation. CPUC-MSCs in particular decrease both Th1 and Th17 cells in Sjögren's syndrome. They regulate several modified interferon-γ inducible factors that play a role in the immunomodulation effect such as indoleamine 2,3-dioxygenase 1, which is similar to an up-regulated diabetes mellitus model and inducible nitric oxide synthase. In vitro studies demonstrated how MSCs and UC-MSCs cultured with specific growth-factors can differentiate into cells exhibiting features of hepatocytes. Interestingly, UC-MSCs express some hepatic markers as albumin, α-fetoprotein, connexin 3 and demonstrate that they are capable of being grafted as well as long-term self-maintenance in recipient livers. Burra et al have standardized pre-in vitro isolation procedures to obtain a UC-MSCs population with hepatogenic properties that can be used for in vivo transplantation. Mice with UC-MSC transplants demonstrated a tendency to resolve liver damage rapidly, influencing inflammation in liver antioxidant enzyme activity and the inhibition of myofibroblasts and stellate cell activation.
Osteoarthritis is a degenerative chronic disease characterized by the degeneration and destruction of articular cartilage due to chondrocyte hypertrophy and apoptosis, together with changes in subchondral bone and osteophyte formation. Evidence shows that a soluble factor, named Kartogenin, is capable of differentiating MSCs into chondrocytes, thereby allowing new cartilage formation. Moreover, MSCs play a role not only in chondrogenic lineage differentiation but also in modulating the immune response that leads to anti-inflammatory effects. The UC-MSCs are another potential cell source for treating osteoarthritis characterized by a high expression of hyaluronic acid, sulfated glycosaminoglycans, and collagen. They exhibit CD276 that are observed in undifferentiated chondrocyte, indicating the immune privilege of UC-MSCs.
UC-MSCs are currently being studied in scaffolds smeared with human UC-MSCs with the aim of cartilage regeneration specific to three-dimensional polylactide-co-glycolide in rabbit models with a chondral defect, which has exhibited positive results. Evidence has shown the ability of transplanted MSCs-derived neural stem cells to follow lineage under specific neuronal growth-factors, to survive and differentiate into progenitors or neuron-like cells expressing neuron-specific markers such as nestin, glial fibrillary acidic protein, β -tubulin III, neuron-specific protein TH, and neuron-specific enolase. Intracerebrally transplanted UC-MSCs can reach the ischemic brain injury in rat models. After implantation, UC-MSCs are detectable in the damaged area expressing neuron-specific markers,. Moreover, a reduction in the number of activated microglia, blocking immune cell infiltration activity, as well as a remarkable reduction of the extensive neuronal damage were observed, occurring during the ischemia-reperfusion and demonstrating the cytoprotective activity of UC-MSCs. This cytoprotective activity is mostly correlated with the immune-regulatory effect of UC-MSCs transplanted due to the modulation and scavenging of the host body's immune response cells under inflammatory conditions as a result of a stroke. They can also enhance the proliferation of endogenous neurogenesis by suppressing apoptosis, secreting neurotrophic factors and inducing vascularization and angiogenesis. A similar effect on traumatic brain injury in rat models was investigated, where UC-MSCs transplantation combined with hyperbaric oxygen treatment resulted in the significant recovery of neurological and cognitive functions. This was also noted in rat models with spinal cord injury where intravenous or intraspinal transplantation of UC-MSCs showed a neuroprotective effect. There are interesting studies concerning the effect of UC-MSCs in some neurodegenerative diseases such as Parkinson's disease. Parkinson's disease is characterized by a continuous dopaminergic cell loss in the nigrostriatal dopaminergic system at the basal ganglia. Authors demonstrated that the transplantation of neuronal differentiation into a dopaminergic phenotype of UC-MSCs in a Parkinson's disease rat model can reduce the symptoms of the disease. Liu et al, investigating the protective effect of UC-MSCs related with a multifunctional mediator, hepatocyte growth factor on the Parkinson's disease cell model, showed the ability of UC-MSCs + hepatocyte growth factor in promoting the regeneration of cells damaged by Parkinson's disease through the regulation of intracellular Ca2+ levels.
Endometriosis is a common, benign, estrogen-dependent and chronic gynecological disorder characterized by the presence of endometrial glands and stroma outside the uterine cavity that cause chronic pelvic pain and infertility,,,,,,,,,. Several non-resolutive strategies, both surgical and medical, are used against this disease,,, but today stem cell therapy is a promising new and unprecedented strategy. Among the several sources of stem cells, UC-MSCs are the strongest candidates for cell-based therapy. The presence of nerve fibers in endometriosis lesions are well known in literature and they play a role in both pathogenic and symptomatic manifestation,.
UC-MSCs have a specific use in therapies that include the use of cells. Moreover, they demonstrate anticancer effects on solid tumors mediated by cell-to-cell and/or non-cellular contact mechanisms. When UC-MSCs were used in mice with mammary adenocarcinomas, they demonstrated the ability to migrate to metastatic tumor sites, suggesting their homing abilities. This anticancer effect with a reduction of growth rate was observed also in ovarian cancer, osteosarcoma and breast adenocarcinoma,,,,,,,,,,. Several molecules are produced by UC-MSCs, including cytokines, glycosaminoglycans, hyaluronic acid, chondroitin sulfate, cell adhesion molecules, and growth factors, which play a role in the anticancer effect,,,,,,,,,.
3.6. Human protocols
Several in vitro and in vivo studies have shown already that UC-MSCs are safe and non-tumorigenic both in laboratory animals and non-human primates, and some clinical trials have already started. For example, MSCs, UC-MSCs included, can be administered to patients with autoimmune and chronic diseases such as Crohn's disease. Some phase 3 clinical trials are currently ongoing with the aim to confirm the safety and the efficacy of this new therapy. Multiple administration of both autologous and allogeneic MSCs, derived from various sources including bone marrow, adipose tissue, and UC treatment, are feasible and have not been associated with any serious adverse event; principally, no tumor formation has been documented in humans until now. Furthermore, studies are underway in order to confirm the efficacy in fistulizing Crohn's disease, and although stem cell therapy is not already a standard treatment for inflammatory bowel diseases, it may become a useful treatment, especially for severe or recurrent inflammatory bowel disease patients. Multiple sclerosis is an immunologically mediated disease of the central nervous system. Several clinical trials were done to investigate the safety and the possible use of MSCs in multiple sclerosis, UC-MSCs included. Hou et al underlined the effectiveness and the safety of UC-MSCs, and they also demonstrated that the inflammatory activity was significantly reduced after treatment. Furthermore, no other clinical relapse and no new magnetic resonance imaging lesions were detected in a 4-year treatment period. This evidence highlights the need to proceed with clinical trials in order to explore MSCs transplantation as a potential new therapy for patients with aggressive multiple sclerosis.
Hypertensive diseases during pregnancy affect almost 10% of women worldwide and are categorized into gestational hypertension, chronic hypertension, and preeclampsia/eclampsia,,,,,,,,. UC-MSCs in patients with preeclampsia show high expression of neuroglial markers, suggesting a commitment to neuroglial differentiation, thus transplantation of exogenous uncommitted MSCs may be a viable option for the treatment of preeclampsia,,.
3.7. Cell-free therapy and MSCs as drug vehicles
Although our systematic review focused on UC-MSCs, we must consider another two aspects in the clinical and therapeutic application of stem cells. The first is the cell-free therapy through microvesicles and exosomes derived from stem cells. Exosomes, small lipid vesicles of 40-130 nm, and microvesicles, larger than exosomes (100-1 000 nm), are included in the larger group of extracellular vesicles and they are secreted from MSCs. Some studies, in fact, affirm that the MSCs play a regenerative role through a paracrine mechanism microvesicle-mediated,. Extracellular vesicles have the ability to carry nucleic acids, proteins and lipids with several roles: in biochemical processes by donating miRNAs that can silence the RNA translation, in inflammation by carrying and transferring inflammatory cytokines, in cell-to-cell communication,. Furthermore, the RNAs carried by extracellular vesicles maintain their function showing the role of extracellular vesicles in epigenetic signalling. For these reasons, microvesicles and exosomes have shown to influence injuries, infections and diseases with a high number of clinical and therapeutic applications: they have shown a cardio, renal and neuroprotective activity, a role in pancreas recovery, pneumonia, pulmonary hypertension, acute respiratory disease syndrome, the prevention of silico-induced lung fibrosis, against liver fibrosis,. Furthermore, they help re-epithelization by inducing cellular proliferation and angiogenesis and they have shown an immunomodulatory role in systemic lupus erythematosus. However, further studies are needed to evaluate the possible therapeutic application of extracellular vesicles in clinical practice. The second aspect is the drug delivery using MSCs as vehicles. MSCs, in fact, have some important advantages in target therapy due to their homing and self-maintenance capability and inflammatory microenvironment interaction. MSCs have been engineered to express anti-proliferative, pro-apoptotic and anti-angiogenic factors for the treatment of several diseases. The most common application is for the treatment of cancer: MSCs, in fact, can localize and integrate into tumor stroma and deliver anti-cancer agents or oncolytic viruses. In the end, MSCs can play in different ways a crucial role in future therapies.
| 4. Discussion|| |
Among MSCs sources, UC-MSCs as a resource seem to possess some brilliant advantages. UC-MSCs can be collected by a simple procedure after delivery, reusing a waste product and applying it for autologous or allogeneic procedures. Furthermore, these cells show multipotency, low immunogenicity, and immunosuppressive activity. These properties give hope for several different clinical applications. Several pre-clinical in vitro and in vivo studies have shown the safety and the ability of these special cells in homing, adhesion, proliferation and differentiation into specific lineages and functions; the capacity to reply to surrounding signals, conditioning the behaviour of neighbour cells, as well as the capacity to regulate cellular and tissue processes such as tumorigenesis, inflammation, apoptosis and proliferation. These qualities are opening up new therapeutical scenarios, as some clinical trials are currently demonstrating for different degenerative, chronic and inflammatory diseases.
Conflict of interest statement
The authors declare that they have no conflict of interest.
| References|| |
Elahi KC, Klein G, Avci-Adali M, Sievert KD, MacNeil S, Aicher WK. Human mesenchymal stromal cells from different sources diverge in their expression of cell surface proteins and display distinct differentiation patterns. Stem Cells Int
Owen M, Friedenstein AJ. Stromal stem cells: Marrow-derived osteogenic precursors. Ciba Found Symp
Cignini P, Laganà AS, Retto A, Vitale SG. Knotting on heaven's door: 3D color Doppler ultrasound imaging of a true cord knot. Arch Gynecol Obstet
Volpe G, Buonadonna AL, Volpe P, Lituania M, Volpe N, Gentile M. Prenatal diagnosis and the clinical significance of discordant umbilical arteries (DUA). Ital J Gynaecol Obstet
Donati L, Giovannini G, Marziani F, Sbaraglia M, Passalacqua G. Fetal death due to umbilical cord thrombosis in association with a swallowed amniotic string. Ital J Gynaecol Obstet
Romanov YA, Balashova EE, Volgina NE, Kabaeva NV, Dugina TN, Sukhikh GT. Isolation of multipotent mesenchymal stromal cells from cryopreserved human umbilical cord tissue. Bull Exp Biol Med
Tocci A, Luchetti L, Isacchi G, De Rossi G, Arduini D. Recent advances in the biology of fetal/cord blood stem cells. Ital J Gynaecol Obstet
Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luriá EA, et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro
colony assay method. Exp Hematol
Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science
Caplan AI. Mesenchymal stem cells. J Orthop Res
Xu Y, Malladi P, Wagner DR, Longaker MT. Adipose-derived mesenchymal cells as a potential cell source for skeletal regeneration. Curr Opin Mol Ther
Salingcarnboriboon R, Yoshitake H, Tsuji K, Obinata M, Amagasa T, Nifuji A, et al. Establishment of tendon-derived cell lines exhibiting pluripotent mesenchymal stem cell-like property. Exp Cell Res
Shi S, Gronthos S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J Bone Miner Res
Harris DT, Rogers I. Umbilical cord blood: A unique source of pluripotent stem cells for regenerative medicine. Curr Stem Cell Res Ther
Reyes-Muñoz E, Sathyapalan T, Rossetti P, Shah M, Long M, Buscema M, et al. Polycystic ovary syndrome: Implication for drug metabolism on assisted reproductive techniques-A literature review. Adv Ther
Igura K, Zhang X, Takahashi K, Mitsuru A, Yamaguchi S, Takashi TA. Isolation and characterization of mesenchymal progenitor cells from chorionic villi of human placenta. Cytotherapy
Seshareddy K, Troyer D, Weiss ML. Method to isolate mesenchymal-like cells from Wharton's Jelly of umbilical cord. Methods Cell Biol
Chang YJ, Tseng CP, Hsu LF, Hsieh TB, Hwang SM. Characterization of two populations of mesenchymal progenitor cells in umbilical cord blood. Cell Biol Int
Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol
Jeon YJ, Kim J, Cho JH, Chung HM, Chae JI. Comparative analysis of human mesenchymal stem cells derived from bone marrow, placenta, and adipose tissue as sources of cell therapy. J Cell Biochem
Fekete N, Rojewski MT, Fürst D, Kreja L, Ignatius A, Dausend J, et al. GMP-compliant isolation and large-scale expansion of bone marrow-derived MSC. PLoS One
Veryasov VN, Savilova AM, Buyanovskaya OA, Chulkina MM, Pavlovich S V, Sukhikh GT. Isolation of mesenchymal stromal cells from extraembryonic tissues and their characteristics. Bull Exp Biol Med
Chatzistamatiou TK, Papassavas AC, Michalopoulos E, Gamaloutsos C, Mallis P, Gontika I, et al. Optimizing isolation culture and freezing methods to preserve Wharton's jelly's mesenchymal stem cell (MSC) properties: An MSC banking protocol validation for the Hellenic Cord Blood Bank. Transfusion
Hua J, Gong J, Meng H, Xu B, Yao L, Qian M, et al. Comparison of different methods for the isolation of mesenchymal stem cells from umbilical cord matrix: Proliferation and multilineage differentiation as compared to mesenchymal stem cells from umbilical cord blood and bone marrow. Cell Biol Int
2013. Doi: 10.1002/cbin.10188.
Conconi MT, Burra P, Di Liddo R, Calore C, Turetta M, Bellini S, et al. CD105(+) cells from Wharton's jelly show in vitro
and in vivo
myogenic differentiative potential. Int J Mol Med
Romanov YA, Svintsitskaya VA, Smirnov VN. Searching for alternative sources of postnatal human mesenchymal stem cells: Candidate MSC-like cells from umbilical cord. Stem Cells
Alunno A, Montanucci P, Bistoni O, Basta G, Caterbi S, Pescara T, et al. In vitro
immunomodulatory effects of microencapsulated umbilical cord Wharton jelly-derived mesenchymal stem cells in primary Sjögren's syndrome. Rheumatology (Oxford)
Xu M, Liu YL, Chen C, Liao L, Zhang Y, Chen H. Comparison of immunologic regulatory characteristics of mesenchymal stem cells derived from human umbilical cord amnion and adult bone marrow. Zhongguo Shi Yan Xue Ye Xue Za Zhi
Ma L, Feng X, Cui B, Law F, Jiang X, Yang LY, et al. Human umbilical cord Wharton's jelly-derived mesenchymal stem cells differentiation into nerve-like cells. Chin Med J (Engl)
Kadivar M, Khatami S, Mortazavi Y, Shokrgozar MA, Taghikhani M, Soleimani M. In vitro
cardiomyogenic potential of human umbilical vein-derived mesenchymal stem cells. Biochem Biophys Res Commun
 Yang H, Sun J, Li Y, Duan WM, Bi J, Qu T. Human umbilical cord-derived mesenchymal stem cells suppress proliferation of PHA-activated lymphocytes in vitro
by inducing CD4(+)CD25(high)CD45RA(+) regulatory T cell production and modulating cytokine secretion. Cell Immunol
Chatterjee D, Marquardt N, Tufa DM, Hatlapatka T, Hass R, Kasper C, et al. Human umbilical cord-derived mesenchymal stem cells utilize activin-A to suppress interferon-γ production by natural killer cells. Front Immunol
Kim HS, Shin TH, Lee BC, Yu KR, Seo Y, Lee S, et al. Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology
Sala E, Genua M, Petti L, Anselmo A, Arena V, Cibella J, et al. Mesenchymal stem cells reduce colitis in mice via release of TSG6, independently of their localization to the intestine. Gastroenterology
Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature
Phillips JM, Parish NM, Raine T, Bland C, Sawyer Y, De La Peña H, et al. Type 1 diabetes development requires both CD4+
T cells and can be reversed by non-depleting antibodies targeting both T cell populations. Rev Diabet Stud
Patel DD, Kuchroo VK. Th17 cell pathway in human immunity: Lessons from genetics and therapeutic interventions. Immunity
Vitale SG, Laganà AS, Nigro A, La Rosa VL, Rossetti P, Rapisarda AMC, et al. Peroxisome proliferator-activated receptor modulation during metabolic diseases and cancers: Master and minions. PPAR Res
Laganà AS, Vitale SG, Nigro A, Sofo V, Salmeri FM, Rossetti P, et al. Pleiotropic actions of peroxisome proliferator-activated receptors (PPARs) in dysregulated metabolic homeostasis, inflammation and cancer: Current evidence and future perspectives. Int J Mol Sci
(7): pii: E999.
Montanucci P, Alunno A, Basta G, Bistoni O, Pescara T, Caterbi S, et al. Restoration of t cell substes of patients with type 1 diabetes mellitus by microencapsulated human umbilical cord Wharton jelly-derived mesenchymal stem cells: An in vitro
study. Clin Immunol
Campard D, Lysy PA, Najimi M, Sokal EM. Native umbilical cord matrix stem cells express hepatic markers and differentiate into hepatocyte-like cells. Gastroenterology
Burra P, Arcidiacono D, Bizzaro D, Chioato T, Di Liddo R, Banerjee A, et al. Systemic administration of a novel human umbilical cord mesenchymal stem cells population accelerates the resolution of acute liver injury. BMC Gastroenterol
Yan M, Sun M, Zhou Y, Wang W, He Z, Tang D, et al. Conversion of human umbilical cord mesenchymal stem cells in Wharton's jelly to dopamine neurons mediated by the Lmx1a and neurturin in vitro:
Potential therapeutic application for Parkinson's disease in a rhesus monkey model. PLoS One
Xia G, Hong X, Chen X, Lan F, Zhang G, Liao L. Intracerebral transplantation of mesenchymal stem cells derived from human umbilical cord blood alleviates hypoxic ischemic brain injury in rat neonates. J Perinat Med
Lees JS, Sena ES, Egan KJ, Antonic A, Koblar SA, Howells DW, et al. Stem cell-based therapy for experimental stroke: A systematic review and meta-analysis. Int J Stroke
Zhu Y, Guan Y, Huang H, Wang Q. Human umbilical cord blood mesenchymal stem cell transplantation suppresses inflammatory responses and neuronal apoptosis during early stage of focal cerebral ischemia in rabbits. Acta Pharmacol Sin
Li Y, Hu G, Cheng Q. Implantation of human umbilical cord mesenchymal stem cells for ischemic stroke: Perspectives and challenges. Front Med
Zhou HX, Liu ZG, Liu XJ, Chen QX. Umbilical cord-derived mesenchymal stem cell transplantation combined with hyperbaric oxygen treatment for repair of traumatic brain injury. Neural Regen Res
Yeng CH, Chen PJ, Chang HK, Lo WY, Wu CC, Chang CY, et al. Attenuating spinal cord injury by conditioned medium from human umbilical cord blood-derived CD34+
cells in rats. Taiwan J Obstet Gynecol
Shetty P, Thakur AM, Viswanathan C. Dopaminergic cells, derived from a high efficiency differentiation protocol from umbilical cord derived mesenchymal stem cells, alleviate symptoms in a Parkinson's disease rodent model. Cell Biol Int
Liu XS, Li JF, Wang SS, Wang YT, Zhang YZ, Yin H-L, et al. Human umbilical cord mesenchymal stem cells infected with adenovirus expressing HGF promote regeneration of damaged neuron cells in a Parkinson's disease model. Biomed Res Int
Giudice LC. Clinical practice: Endometriosis. N Engl J Med
Laganà AS, La Rosa VL, Rapisarda AMC, Valenti G, Sapia F, Chiofalo B, et al. Anxiety and depression in patients with endometriosis: Impact and management challenges. Int J Womens Health
Van Aken MAW, Oosterman JM, van Rijn CM, Ferdek MA, Ruigt GSF, Peeters BWMM, et al. Pain cognition versus pain intensity in patients with endometriosis: Toward personalized treatment. Fertil Steril
Vitale SG, La Rosa VL, Rapisarda AMC, Laganà AS. Impact of endometriosis on quality of life and psychological well-being. J Psychosom Obstet Gynaecol
Maniglio P, Ricciardi E, Meli F, Vitale SG, Noventa M, Vitagliano A, et al. Catamenial pneumothorax caused by thoracic endometriosis. Radiol Case Reports
Vitale SG, La Rosa VL, Vitagliano A, Noventa M, Laganà FM, Ardizzone A, et al. Sexual function and quality of life in patients affected by deep infiltrating endometriosis: Current evidence and future perspectives. J Endometr Pelvic Pain Disord
Vitale SG, Capriglione S, Peterlunger I, La Rosa VL, Vitagliano A, Noventa M, et al. The role of oxidative stress and membrane transport systems during endometriosis: A fresh look at a busy corner. Oxid Med Cell Longev
Vitale SG, La Rosa VL, Rapisarda AMC, Laganà AS. Endometriosis and infertility: The impact on quality of life and mental health. J Endometr Pelvic Pain Disord
Laganà AS, Vitale SG, Salmeri FM, Triolo O, Ban Frangež H, Vrtačnik-Bokal E, et al. Unus pro omnibus, omnes pro uno: A novel, evidence-based, unifying theory for the pathogenesis of endometriosis. Med Hypotheses
Sourial S, Tempest N, Hapangama DK. Theories on the pathogenesis of endometriosis. Int J Reprod Med
Laganà AS, Vitale SG, Trovato MA, Palmara VI, Rapisarda AMC, Granese R, et al. Full-thickness excision versus shaving by laparoscopy for intestinal deep infiltrating endometriosis: Rationale and potential treatment options. Biomed Res Int
Vercellini P, Somigliana E, Viganò P, Abbiati A, Daguati R, Crosignani PG. Endometriosis: Current and future medical therapies. Best Pract Res Clin Obstet Gynaecol
Laganà AS, Vitale SG, Granese R, Palmara V, Ban Frangež H, Vrtačnik-Bokal E, et al. Clinical dynamics of dienogest for the treatment of endometriosis: From bench to bedside. Expert Opin Drug Metab Toxicol
Laganà AS, Salmeri FM, Vitale SG, Triolo O, Götte M. Stem cell trafficking during endometriosis: May epigenetics play a pivotal role? Reprod Sci
Xu LN, Lin N, Xu BN, Li JB, Chen SQ. Effect of human umbilical cord mesenchymal stem cells on endometriotic cell proliferation and apoptosis. Genet Mol Res
Chen Y, Li D, Zhang Z, Takushige N, Kong BH, Wang GY. Effect of human umbilical cord mesenchymal stem cells transplantation on nerve fibers of a rat model of endometriosis. Int J Fertil Steril
Yang Y, Fan B, Tong X. Direct interactions between human mesenchymal stem cells and ovarian cancer cells. Zhonghua Yi Xue Za Zhi
Zhang Y, Wang J, Ren M, Li M, Chen D, Chen J, et al. Gene therapy of ovarian cancer using IL-21-secreting human umbilical cord mesenchymal stem cells in nude mice. J Ovarian Res
Vitale SG, Capriglione S, Zito G, Lopez S, Gulino FA, Di Guardo F, et al. Management of endometrial, ovarian and cervical cancer in the elderly: Current approach to a challenging condition. Arch Gynecol Obstet
Vitale SG, Laganà AS, Capriglione S, Angioli R, La Rosa VL, Lopez S, et al. Target therapies for uterine carcinosarcomas: Current evidence and future perspectives. Int J Mol Sci
(5): pii: E1100.
Subramanian A, Shu-Uin G, Kae-Siang N, Gauthaman K, Biswas A, Choolani M, et al. Human umbilical cord Wharton's jelly mesenchymal stem cells do not transform to tumor-associated fibroblasts in the presence of breast and ovarian cancer cells unlike bone marrow mesenchymal stem cells. J Cell Biochem
Zhao W, Cheng J, Shi P, Huang J. Human umbilical cord mesenchymal stem cells with adenovirus-mediated interleukin 12 gene transduction inhibits the growth of ovarian carcinoma cells both in vitro
and in vivo. Nan Fang Yi Ke Da Xue Xue Bao
Bellia A, Vitale SG, Laganà AS, Cannone F, Houvenaeghel G, Rua S, et al. Feasibility and surgical outcomes of conventional and robot-assisted laparoscopy for early-stage ovarian cancer: A retrospective, multicenter analysis. Arch Gynecol Obstet
Rossetti D, Vitale SG, Gulino FA, Rapisarda AMC, Valenti G, Zigarelli M, et al. Laparoendoscopic single-site surgery for the assessment of peritoneal carcinomatosis resectability in patients with advanced ovarian cancer. Eur J Gynaecol Oncol
Vitale SG, Marilli I, Lodato M, Tropea A, Cianci A. The role of cytoreductive surgery in advanced-stage ovarian cancer: A systematic review. Updates Surg
Corrado G, Vizza E, Legge F, Pedone Anchora L, Sperduti I, Fagotti A, et al. Comparison of different surgical approaches for stage IB1 cervical cancer patients: A multi-institution study and a review of the literature. Int J Gynecol Cancer
Vizza E, Chiofalo B, Cutillo G, Mancini E, Baiocco E, Zampa A, et al. Robotic single site radical hysterectomy plus pelvic lymphadenectomy in gynecological cancers. J Gynecol Oncol
Ding DC, Chang YH, Shyu WC, Lin SZ. Human umbilical cord mesenchymal stem cells: A new era for stem cell therapy. Cell Transplant
Valenti G, Vitale SG, Tropea A, Biondi A, Laganà AS. Tumor markers of uterine cervical cancer: A new scenario to guide surgical practice? Updates Surg
Chiofalo B, Palmara V, Laganà AS, Triolo O, Vitale SG, Conway F, et al. Fertility sparing strategies in patients affected by placental site trophoblastic tumor. Curr Treat Options Oncol
Rossetti D, Vitale SG, Tropea A, Biondi A, Laganà AS. New procedures for the identification of sentinel lymph node: Shaping the horizon of future management in early stage uterine cervical cancer. Updates Surg
Bongso A, Fong CY. The therapeutic potential, challenges and future clinical directions of stem cells from the Wharton's jelly of the human umbilical cord. Stem Cell Rev
Cignini P, Vitale SG, Laganà AS, Biondi A, La Rosa VL, Cutillo G. Preoperative work-up for definition of lymph node risk involvement in early stage endometrial cancer: 5-year follow-up. Updates Surg
Vitale SG, Valenti G, Rapisarda AMC, Calì I, Marilli I, Zigarelli M, et al. P16INK4a as a progression/regression tumour marker in LSIL cervix lesions: Our clinical experience. Eur J Gynaecol Oncol
Vitale SG, Valenti G, Biondi A, Rossetti D, Frigerio L. Recent trends in surgical and reconstructive management of vulvar cancer: Review of literature. Updates Surg
Wang M, Cai J, Huang F, Zhu M, Zhang Q, Yang T, et al. Pre-treatment of human umbilical cord-derived mesenchymal stem cells with interleukin-6 abolishes their growth-promoting effect on gastric cancer cells. Int J Mol Med
Ma F, Chen D, Chen F, Chi Y, Han Z, Feng X, et al. Human umbilical cord mesenchymal stem cells promote breast cancer metastasis by interleukin-8- and interleukin-6-dependent induction of CD44(+)/ CD24(-) cells. Cell Transplant
Forbes GM. Mesenchymal stromal cell therapy in Crohn's disease. Dig Dis
Irhimeh MR, Cooney J. Management of inflammatory bowel disease using stem cell therapy. Curr Stem Cell Res Ther
Freedman MS, Bar-Or A, Atkins HL, Karussis D, Frassoni F, Lazarus H, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: Consensus report of the international MSCT study group. Mult Scler
Hou ZL, Liu Y, Mao XH, Wei CY, Meng MY, Liu YH, et al. Transplantation of umbilical cord and bone marrow-derived mesenchymal stem cells in a patient with relapsing-remitting multiple sclerosis. Cell Adhes Migr
Salman H, Shah M, Ali A, Aziz A, Vitale SG. Assessment of relationship of serum neurokinin-B level in the pathophysiology of pre-eclampsia: A case-control study. Adv Ther
Laganà AS, Vitale SG, Sapia F, Valenti G, Corrado F, Padula F, et al. miRNA expression for early diagnosis of preeclampsia onset: Hope or hype? J Matern Neonatal Med
Staelens AS, Vonck S, Molenberghs G, Malbrain MLNG, Gyselaers W. Maternal body fluid composition in uncomplicated pregnancies and preeclampsia: A bioelectrical impedance analysis. Eur J Obstet Gynecol Reprod Biol
Yogev Y, Xenakis EMJ, Langer O. The association between preeclampsia and the severity of gestational diabetes: The impact of glycemic control. Am J Obstet Gynecol
Laganà AS, Giordano D, Loddo S, Zoccali G, Vitale SG, Santamaria A, et al. Decreased endothelial progenitor cells (EPCs) and increased natural killer (NK) cells in peripheral blood as possible early markers of preeclampsia: A case-control analysis. Arch Gynecol Obstet
Chiofalo B, Laganà AS, Vaiarelli A, La Rosa VL, Rossetti D, Palmara V, et al. Do miRNAs play a role in fetal growth restriction? A fresh look to a busy corner. Biomed Res Int
Totaro Aprile F, de Luca G, Bruno MG, Presta L, de Marzi CA, Nicolaci F, et al. Arterial hypertension during pregnancy: An appraisal on risk factors. Ital J Gynaecol Obstet
Locci M, Nazzaro G, De Placido G, Nazzaro A, Montagnani S, Colacurci N, et al. Intrauterine growth retardation in pregnancy induced hypertension. An immunohistochemical interpretation of umbilical artery absent or reversed end diastolic flow. Ital J Gynaecol Obstet
Stella A, Marinangeli S, Grella PV. Intra-uterine growth retardation and pregnancy-induced hypertension: Haemorheological aspects. Ital J Gynaecol Obstet
Wang LL, Yu Y, Guan HB, Qiao C. Effect of human umbilical cord mesenchymal stem cell transplantation in a rat model of preeclampsia. Reprod Sci
Fu L, Liu Y, Zhang D, Xie J, Guan H, Shang T. Beneficial effect of human umbilical cord-derived mesenchymal stem cells on an endotoxin-induced rat model of preeclampsia. Exp Ther Med
Joerger-Messerli M, Brühlmann E, Bessire A, Wagner A, Mueller M, Surbek DV, et al. Preeclampsia enhances neuroglial marker expression in umbilical cord Wharton's jelly-derived mesenchymal stem cells. J Matern Fetal Neonatal Med
Perez-Hernandez J, Redon J, Cortes R. Extracellular vesicles ad therapeutic agents in Systemic Lupus Erythematosus. Int J Mol Sci
(4): pii: E717.
Baglio S.R, Pegtel M, Baldini N. Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol
Panagiotou N, Davies R.W, Selman C, Shiels P.G. Microvesicles as vehicles for tissue regeneration: changing of the guards. Curr Pathobiol Rep
Phinney D.G, Pittenger M.F. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells
Sherman L.S, Shaker M, Mariotti V, Rameshwar P. Mesenchymal stromal/ stem cells in drug therapy: new perspective. Cytotherapy
Gjorgieva D, Zaidman N, Bosnakovski D. Mesenchymal stem cells for anti-cancer drug delivery. Recent Pat Anticancer Drug Discov
|This article has been cited by|
||Therapeutic Potential of Autologous Adipose Derived Mesenchymal Stem Cells in Human POI and Ovarian Aging
| ||Luján Irastorza Jesús Estuardo,Durand Montaño Carlos,Hernández Ramos Roberto,Ávila Pérez Felipe de Jesús,Guerrero Vargas José Juan,Kava Braverman Alejandro,Ávila Rebollar Daniela,Pariente Fernández Maruxa,Paredes Núñez María Angélica,Gabriel de la Rosa Ruiz,Vargas Hernández Víctor Manuel,Ang-Chen Tsai |
| ||Journal of Evolving Stem Cell Research. 2021; 1(3): 5 |
|[Pubmed] | [DOI]|
||The rising role of mesenchymal stem cells in the treatment of COVID-19 infections
| ||KA Al-Anazi,AM Al-Jasser |
| ||Journal of Stem Cell Therapy and Transplantation. 2020; 4(1): 011 |
|[Pubmed] | [DOI]|