Adipose Stem Cells (ASCs) and Stromal Vascular Fraction (SVF) as a Potential Therapy in Combating (COVID-19)-Disease
Gentile Pietro1, *, Sterodimas Aris2
1Department of Surgical Science, University of Rome Tor Vergata, Rome, Italy2Department of Plastic and Reconstructive Surgery, Metropolitan General Hospital, Athens, Greece
通讯作者: Correspondence should be addressed to: Dr. Pietro Gentile, Department of Surgical Science, University of Rome Tor Vergata, Rome, 00133, Italy. Email pietrogentile2004@libero.it.Correspondence should be addressed to: Dr. Pietro Gentile, Department of Surgical Science, University of Rome Tor Vergata, Rome, 00133, Italy. Email pietrogentile2004@libero.it.
收稿日期:2020-03-30
修回日期: 2020-04-22
接受日期: 2020-04-22
网络出版日期: 2020-05-09
版权声明:
2020 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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Abstract
A recent and interesting study reported improved respiratory activity after intravenous administration of mesenchymal stem cells (MSCs) into patients affected by coronavirus disease 2019 (COVID-19). These outcomes displayed that intravenous infiltration of MSCs is a safe and efficacy treatment for COVID-19 pneumonia, a severe acute respiratory illness caused by the coronavirus 2 (SARS-CoV-2). Only 7 patients were treated, but with extraordinary results, opening a new strategy in COVID-19 therapy. Currently, no specific therapies against SARS-CoV-2 are available. The MSCs therapy outcomes reported, are striking, as these cells inhibit the over-activation of the immune system, promoting endogenous repair, by improving the lung microenvironment after the SARS-CoV-2 infection. The MSCs could represent an effective, autologous and safe therapy, and therefore, sharing these published results, here is reported the potential use possibilities in COVID-19 of the most common MSCs represented by Adipose Stem Cells (ASCs).
GentilePietro, SterodimasAris. Adipose Stem Cells (ASCs) and Stromal Vascular Fraction (SVF) as a Potential Therapy in Combating (COVID-19)-Disease[J]. Aging and Disease, 2020, 11(3): 465-469 https://doi.org/10.14336/AD.2020.0422
Introduction
Robert Chunhua Zhao's group [1] reported in a recent study, published in March 2020, an interesting improvement in pulmonary functional activity, into 7 patients affected by Coronavirus Disease 2019 (COVID-19) after a intravenous administration of clinical-grade mesenchymal stem cells (MSCs). The COVID-19, as already known, is a severe acute respiratory illness caused by a new coronavirus named coronavirus 2 (CoV-2) [2-3]. Cov-2 is first appeared in Wuhan, China, but has now disseminated to multiple countries in the world, including Europe, the United Kingdom, and the United States [2-3]. In Europe, the situation is most serious in Italy (www.salute.gov.it) and Spain, while currently the United States seems to be the most affected country in the world.
It is not clear the origin of the virus. Several hypotheses have been reported, without any scientific proof.
Zhou P. et al. [4] in an article published in Nature, Mar 12, 2020, reported that the sequences of 2019-nCoV (SARS-Cov-2) were almost identical and share 79.6% sequence identity to SARS-CoV. In detail, they confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2) as SARS-CoV [4]. They clearly affirm, "We do not yet know the transmission routine of this virus among hosts... Owing to a shortage of specific treatments and considering the relatedness of 2019-nCoV to SARS-CoV, some drugs and pre-clinical vaccines against, SARS-CoV could probably be used to treat this virus" [4].
At the current time, there is no scientific evidence of the first transmission kind, as previously reported, while other notices are mediatic only.
Today, April 22, 2020, as reported by www.worldometers.info/coronavirus/ we have in the World 2,572,805 Coronavirus Cases, 178,551 deaths and 701,552 recovered.
For this reason, it appears to be necessary very quickly test new therapies.
In the ongoing pandemic, the only means available to reduce the infection are represented by travel restrictions, containment measures, and mitigation strategies or as currently in Italy and Spain, the total lockdown.
Starting with the preliminary and precious experience published by Zhao's group [1] we aim to suggest an immediate, easy and safe therapy in Covid-19 patients via the most common and important MSCs represented by ASCs so as to help the research.
Intravenous Infusion of Mesenchymal Stem Cells (MSCs) in Covid-19 patients
In the preliminary study of Robert Chunhua Zhao's group [1], 7 patients affected by SARS-CoV-2, with COVID-19 pneumonia displayed a sensible improvement pulmonary function after several intravenous infusion of clinical-grade MSCs [1]. The results were compared with a little control group composed of 3 patients treated with a placebo.
The authors described the preparation of infusion suspension, suspending a cellular product of MSCs in 100 mL of saline, and reporting the total amount of infused cells was 1 × 106 cells per kg. The infusion was performed for about 40 minutes with a speed of ~40 drops per minute when symptoms still were getting worse [1], then the patients have been observed closely for 14 days. Surprisingly, the study reported that all pulmonary and other symptoms subsided 3 days average later receiving intravenous MSCs infusion without side effects. Extraordinarily, the post-treatment CT imaging showed that pneumonia was significantly decreased, and the major part of treated patients had shown negative results for the SARS-CoV-2 nucleic acid test 1.5 weeks average later the treatment [1].
Starting with this fundamental work, it is necessary to specify that, as reported in the study [1], the MSCs used, were a certified cellular product.
The rationale of the present work is to suggest the possibility to use autologous or allogeneic ASCs intravenously or directly through a ventilation mask (aerosol). Autologous ASCs can be collected and infused quickly while for allogeneic ASCs it is necessary to have a Good Manufacturing Practices (GMP) lab approval.
The potential use of MSCs and ASCs, and their bio-molecular implications in COVID-19
MSCs have been used extensively in cellular therapies, including both pre-clinical and clinical studies [5-8], suggesting their safety and efficacy. The sources of MSCs are principally two: adipose tissue, and bone marrow [9]. Recent studies introduced a new, interesting, and alternative sources of MSCs represented by Dental Pulp Stem Cells (DPSCs) [10], Periodontal Ligament stem cells (PDLSCs) [11], and Oral Stem Cells [12]. The sub-cutaneous adipose tissue offers a significant edge over other sources because it is easily accessible posing the least amount of discomfort to the patient and being easy to use with local anesthesia. Additionally, it is extremely easy to isolate the stem cells from the adipose tissue via minimal manipulation or enzymatic digestion of fat [13, 14].
Minimal manipulation is based on fat mechanical centrifugation and/or filtration, while enzymatic digestion on collagenases uses, as previously described [9, 15-21]. A difference in terms of stem cell amount was reported between procedures [9, 15-21].
A higher quantity of stem cells was observed in adipose tissue compared to bone marrow [22]. MSCs are multi-potent cells that renew on their own, having the capacity to split into cells of mesenchymal origin in vitro as chondrocytes, adipocytes, and osteoblasts. Human ASCs express the classical mesenchymal markers such as CD44, CD73, CD90, CD105 and CD166 [9], and are located in Stromal Vascular Fraction (SVF) portion of sub-cutaneous fat [23]. For these reasons, it is possible to identify the ASCs as the most important representative of MSCs.
MSCs and ASCs with related SVF portion have been used in the immune-mediated inflammatory diseases (graft-versus-host disease and systemic lupus erythematosus) [24, 25], in lower extremity ulcers [26], calvarial defects [27], craniofacial microsomia [28], breast reconstruction [16-19, 29, 30], outcomes of burns and scars [20] with safe and interesting results.
The improved pulmonary and other organs function after MSC infusions in the study of Zhao's group [1], can be attributed both to immune-modulatory that also to the anti-inflammatory MSCs effects, as these cells release many paracrine factors, which interact with immune cells resulting in immunomodulation, and with inflammation decrease [5, 6, 31]. These effects were confirmed by the increased peripheral lymphocytes amount, the decline in the C-reactive protein, and waning of over-activated cytokine-secreting immune cells (CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells) into the blood of treated patients, by mean 4.5 days later the intravenous infusion [1]. Moreover, 10 x RNA-sequencing analysis displayed that infused MSCs were negative for ACE2 and TMPRSS2, which confirmed that these cells were free from COVID-19 infection. The possible implications of MSCs as anti-viral therapy have been cited by also the Kyoto Encyclopedia of Genes and Genomes (KEGG) [1].
Now, the adipose-derived MSCs and related SVF have been routinely used for many years in autologous regenerative therapies, displaying effective and safe results, as previously cited. They could have also a potential allogeneic use via a specific Human Tissue Fat Bio-Bank that lacks at this moment or via GMP laboratory.
Currently, there are 22 clinical trials registered (https://clinicaltrials.gov) to evaluate the MSCs as clinical treatment of patients affected by COVID-19. (https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=Mesenchymal%20Stem%20Cells&cntry=&state=&city=&dist=). Of these clinical trials, in particular, two are on DPSCs, five are on Umbilical Cord Stem Cells (UC-SCs), one is on Mesenchymal Stromal Cells, one on MSCs-Exosomes and two are on ASCs.
It is too early to know if ASCs will be used as part of future treatment options for COVID-19 or similar conditions with significant complications, but there is the potential that the work we are seeing reported on today will become a part of helping patients with COVID-19. In each case, it is necessary to specify that these procedures are possible only if performed and authorized by the GMP lab or EMA in Europe and by FDA in the United States.
ASCs and SVF potential effects through secretory and anti-inflammatory activities
As briefly introduced, SVF contains a larger cellular population, represented by ASCs and Stromal vascular Fraction Cells (SVFs). SVFs and ASCs secrete pro-angiogenic factors, such as Vascular Endothelial Growth Factor (VEGF), platelet-derived growth factors (PDGF), inducing proliferation of endothelial cells, promoting the vascularization, providing physical Extracellular Matrix (ECM) guidance cues that promote endothelial sprouting [17, 18]. Moreover, SVFs and ASCs have immune-modulating proprieties mediated by transforming growth factor-1 (TGF-1), hepatocyte growth factors (HGF) and interferon-γ (INF-γ) [17, 18]. These activities and the early establishment of new micro-capillary networks, which deliver the proper nutrients and oxygen, might contributed to the improved outcomes observed during MSCs infusion in Covid-19 patients.
The high secretory activity makes also SVFs and ASCs, as MSCs, a potentially suitable vehicle for the delivery of drugs molecules in the cellular microenvironment, with the potential aim to regenerate damaged tissue as for to nanotechnologies, drug-loaded exosomes, and micro-RNAs (MiRs) [18]. Several MiRs are present in fat, actively participating in the adipogenesis regulation, adipokine secretion, inflammation, and inter-cellular communications in the tissues. These results provide important insights into Adipocyte-secreted exosomal microRNAs (A-Se-MiRs) function and they suggest evaluating the potential role of A-Se-MiRs in human organs and tissue regeneration [18]. In particular, the situation produced by the COVID-19 in currently April, 2020 as pandemic, in which there is not actually any therapy, any vaccines, must push reflect about the idea that may be necessary resort to our SVFs and ASCs and related MiRs for the cure of human pathologies or organ damages.
Rationale of the ASCs and SVFs use
The adipose-derived MSCs, as ASCs and SVFs in which they are contained (1mL of fat tissue offers 100.000 SVFs of which 1% - 3% are ASCs = 1.000/3.000), can be collected by 100mL of fat tissue, obtained by a very simple, fast and safe gently liposuction, performed also in local anesthesia, from the abdomen, flank and thighs regions [15-17, 20].
With 100mL of processed fat via minimal manipulation, it is possible to obtain an average of 1 × 107 SVFs containing ASCs [15-18].
Robert Chunhua Zhao's group [1] reported the use of 1 × 106 MSCs per Kg of weight. For this reason, it is possible to think that they infused 75 × 106 MSCs (75.000.000 MSCs) for each patient, hypothesizing a weight mean of 75Kg (data not published). Using the minimal manipulation of fat tissue could be necessary to collect a 500-1000mL average of fat tissue, to generate 50 × 106 - 100 × 106 50.000.000-100.000.000 adipose-derived MSCs. Using enzymatic digestion of fat tissue, it is possible to divide two different procedures: manual and automatic extraction.
From adipose tissue, by manual extraction, it was obtained approximately 250,000 ± 34,782 nucleated SVFs cells per each mL of fat tissue; on the other hand, by the automatic extractor, the cell yield was approximately 50,000 ± 6,956 nucleated SVFs cells per ml of fat tissue (p < 0.01) [20]. In the first case, 25 × 106 (25.000.000) nucleated SVFs cells can be obtained by 100mL of fat tissue, and 300mL of fat (average 150-400mL) would be the right amount to obtain average 75 × 106 75,000,000 cells.
Alternatively, using a few each mL of fat tissue for each patient (5-10mL) would be necessary to perform extensive manipulation via GMP lab, to obtain the same quantity of cells in form of the cellular product like as which used by Zhao's group [1]. In Italy for example, we have 17 GMP authorized lab, but there are not studies published in this sense.
All these procedures of fat tissue manipulation, aimed to obtain an SVFs pellet containing ASCs, are regulated by the European rules (1394/2007 EC) and EMA/CAT recommendations (20 June 2014 EMA/CAT/600280/ 2010 Rev 1) [17, 18, 21].
Conclusions
It is not more possible to accept the idea, that for a viral pandemic, at the current day, it is necessary to stay at home to avoid contagion, like Middle Ages, or it is necessary to be hospitalized, in intensive therapy to continue to breathe.
For this reason, ASCs, SVFs both autologous and allogeneic, A-Se-MiR and each type of MSCs may offer new and alternative approaches for the Covid-19 therapy. ASCs and SVFs could be infused today quickly and safely.
SinjariB, PizzicannellaJ, D'AuroraM, et al. (2019).
Curcumin/Liposome Nanotechnology as Delivery Platform for Anti-inflammatory Activities via NFkB/ERK/pERK Pathway in Human Dental Pulp Treated With 2-HydroxyEthyl MethAcrylate (HEMA)
A comparative translational study: the combined use of enhanced stromal vascular fraction and platelet-rich plasma improves fat grafting maintenance in breast reconstruction
Engineered Fat Graft Enhanced with Adipose-Derived Stromal Vascular Fraction Cells for Regenerative Medicine: Clinical, Histological and Instrumental Evaluation in Breast Reconstruction
Adipose-derived stromal vascular fraction cells and platelet-rich plasma: basic and clinical evaluation for cell-based therapies in patients with scars on the face
Impact of the Different Preparation Methods to Obtain Human Adipose-Derived Stromal Vascular Fraction Cells (AD-SVFs) and Human Adipose-Derived Mesenchymal Stem Cells (AD-MSCs): Enzymatic Digestion Versus Mechanical Centrifugation
CT-04 Safety and efficacy of allogeneic umbilical cord-derived mesenchymal stem cells (MSCs) in patients with systemic lupus erythematosus: results of an open-label phase I study
Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia
12
2020
... Robert Chunhua Zhao's group [1] reported in a recent study, published in March 2020, an interesting improvement in pulmonary functional activity, into 7 patients affected by Coronavirus Disease 2019 (COVID-19) after a intravenous administration of clinical-grade mesenchymal stem cells (MSCs). The COVID-19, as already known, is a severe acute respiratory illness caused by a new coronavirus named coronavirus 2 (CoV-2) [2-3]. Cov-2 is first appeared in Wuhan, China, but has now disseminated to multiple countries in the world, including Europe, the United Kingdom, and the United States [2-3]. In Europe, the situation is most serious in Italy (www.salute.gov.it) and Spain, while currently the United States seems to be the most affected country in the world. ...
... Starting with the preliminary and precious experience published by Zhao's group [1] we aim to suggest an immediate, easy and safe therapy in Covid-19 patients via the most common and important MSCs represented by ASCs so as to help the research. ...
... In the preliminary study of Robert Chunhua Zhao's group [1], 7 patients affected by SARS-CoV-2, with COVID-19 pneumonia displayed a sensible improvement pulmonary function after several intravenous infusion of clinical-grade MSCs [1]. The results were compared with a little control group composed of 3 patients treated with a placebo. ...
... ], 7 patients affected by SARS-CoV-2, with COVID-19 pneumonia displayed a sensible improvement pulmonary function after several intravenous infusion of clinical-grade MSCs [1]. The results were compared with a little control group composed of 3 patients treated with a placebo. ...
... The authors described the preparation of infusion suspension, suspending a cellular product of MSCs in 100 mL of saline, and reporting the total amount of infused cells was 1 × 106 cells per kg. The infusion was performed for about 40 minutes with a speed of ~40 drops per minute when symptoms still were getting worse [1], then the patients have been observed closely for 14 days. Surprisingly, the study reported that all pulmonary and other symptoms subsided 3 days average later receiving intravenous MSCs infusion without side effects. Extraordinarily, the post-treatment CT imaging showed that pneumonia was significantly decreased, and the major part of treated patients had shown negative results for the SARS-CoV-2 nucleic acid test 1.5 weeks average later the treatment [1]. ...
... ], then the patients have been observed closely for 14 days. Surprisingly, the study reported that all pulmonary and other symptoms subsided 3 days average later receiving intravenous MSCs infusion without side effects. Extraordinarily, the post-treatment CT imaging showed that pneumonia was significantly decreased, and the major part of treated patients had shown negative results for the SARS-CoV-2 nucleic acid test 1.5 weeks average later the treatment [1]. ...
... Starting with this fundamental work, it is necessary to specify that, as reported in the study [1], the MSCs used, were a certified cellular product. ...
... The improved pulmonary and other organs function after MSC infusions in the study of Zhao's group [1], can be attributed both to immune-modulatory that also to the anti-inflammatory MSCs effects, as these cells release many paracrine factors, which interact with immune cells resulting in immunomodulation, and with inflammation decrease [5, 6, 31]. These effects were confirmed by the increased peripheral lymphocytes amount, the decline in the C-reactive protein, and waning of over-activated cytokine-secreting immune cells (CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells) into the blood of treated patients, by mean 4.5 days later the intravenous infusion [1]. Moreover, 10 x RNA-sequencing analysis displayed that infused MSCs were negative for ACE2 and TMPRSS2, which confirmed that these cells were free from COVID-19 infection. The possible implications of MSCs as anti-viral therapy have been cited by also the Kyoto Encyclopedia of Genes and Genomes (KEGG) [1]. ...
... ]. These effects were confirmed by the increased peripheral lymphocytes amount, the decline in the C-reactive protein, and waning of over-activated cytokine-secreting immune cells (CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells) into the blood of treated patients, by mean 4.5 days later the intravenous infusion [1]. Moreover, 10 x RNA-sequencing analysis displayed that infused MSCs were negative for ACE2 and TMPRSS2, which confirmed that these cells were free from COVID-19 infection. The possible implications of MSCs as anti-viral therapy have been cited by also the Kyoto Encyclopedia of Genes and Genomes (KEGG) [1]. ...
... ]. Moreover, 10 x RNA-sequencing analysis displayed that infused MSCs were negative for ACE2 and TMPRSS2, which confirmed that these cells were free from COVID-19 infection. The possible implications of MSCs as anti-viral therapy have been cited by also the Kyoto Encyclopedia of Genes and Genomes (KEGG) [1]. ...
... Robert Chunhua Zhao's group [1] reported the use of 1 × 106 MSCs per Kg of weight. For this reason, it is possible to think that they infused 75 × 106 MSCs (75.000.000 MSCs) for each patient, hypothesizing a weight mean of 75Kg (data not published). Using the minimal manipulation of fat tissue could be necessary to collect a 500-1000mL average of fat tissue, to generate 50 × 106 - 100 × 106 50.000.000-100.000.000 adipose-derived MSCs. Using enzymatic digestion of fat tissue, it is possible to divide two different procedures: manual and automatic extraction. ...
... Alternatively, using a few each mL of fat tissue for each patient (5-10mL) would be necessary to perform extensive manipulation via GMP lab, to obtain the same quantity of cells in form of the cellular product like as which used by Zhao's group [1]. In Italy for example, we have 17 GMP authorized lab, but there are not studies published in this sense. ...
A novel coronavirus emerging in China - key questions for impact assessment
2
2020
... Robert Chunhua Zhao's group [1] reported in a recent study, published in March 2020, an interesting improvement in pulmonary functional activity, into 7 patients affected by Coronavirus Disease 2019 (COVID-19) after a intravenous administration of clinical-grade mesenchymal stem cells (MSCs). The COVID-19, as already known, is a severe acute respiratory illness caused by a new coronavirus named coronavirus 2 (CoV-2) [2-3]. Cov-2 is first appeared in Wuhan, China, but has now disseminated to multiple countries in the world, including Europe, the United Kingdom, and the United States [2-3]. In Europe, the situation is most serious in Italy (www.salute.gov.it) and Spain, while currently the United States seems to be the most affected country in the world. ...
... ]. Cov-2 is first appeared in Wuhan, China, but has now disseminated to multiple countries in the world, including Europe, the United Kingdom, and the United States [2-3]. In Europe, the situation is most serious in Italy (www.salute.gov.it) and Spain, while currently the United States seems to be the most affected country in the world. ...
World Health Organization declares Global Emergency: A review of the 2019 Novel Coronavirus (COVID-19)
2
2020
... Robert Chunhua Zhao's group [1] reported in a recent study, published in March 2020, an interesting improvement in pulmonary functional activity, into 7 patients affected by Coronavirus Disease 2019 (COVID-19) after a intravenous administration of clinical-grade mesenchymal stem cells (MSCs). The COVID-19, as already known, is a severe acute respiratory illness caused by a new coronavirus named coronavirus 2 (CoV-2) [2-3]. Cov-2 is first appeared in Wuhan, China, but has now disseminated to multiple countries in the world, including Europe, the United Kingdom, and the United States [2-3]. In Europe, the situation is most serious in Italy (www.salute.gov.it) and Spain, while currently the United States seems to be the most affected country in the world. ...
... -3]. In Europe, the situation is most serious in Italy (www.salute.gov.it) and Spain, while currently the United States seems to be the most affected country in the world. ...
A pneumonia outbreak associated with a new coronavirus of probable bat origin
3
2020
... Zhou P. et al. [4] in an article published in Nature, Mar 12, 2020, reported that the sequences of 2019-nCoV (SARS-Cov-2) were almost identical and share 79.6% sequence identity to SARS-CoV. In detail, they confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2) as SARS-CoV [4]. They clearly affirm, "We do not yet know the transmission routine of this virus among hosts... Owing to a shortage of specific treatments and considering the relatedness of 2019-nCoV to SARS-CoV, some drugs and pre-clinical vaccines against, SARS-CoV could probably be used to treat this virus" [4]. ...
... ] in an article published in Nature, Mar 12, 2020, reported that the sequences of 2019-nCoV (SARS-Cov-2) were almost identical and share 79.6% sequence identity to SARS-CoV. In detail, they confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2) as SARS-CoV [4]. They clearly affirm, "We do not yet know the transmission routine of this virus among hosts... Owing to a shortage of specific treatments and considering the relatedness of 2019-nCoV to SARS-CoV, some drugs and pre-clinical vaccines against, SARS-CoV could probably be used to treat this virus" [4]. ...
... [4]. ...
Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation
2
2012
... MSCs have been used extensively in cellular therapies, including both pre-clinical and clinical studies [5-8], suggesting their safety and efficacy. The sources of MSCs are principally two: adipose tissue, and bone marrow [9]. Recent studies introduced a new, interesting, and alternative sources of MSCs represented by Dental Pulp Stem Cells (DPSCs) [10], Periodontal Ligament stem cells (PDLSCs) [11], and Oral Stem Cells [12]. The sub-cutaneous adipose tissue offers a significant edge over other sources because it is easily accessible posing the least amount of discomfort to the patient and being easy to use with local anesthesia. Additionally, it is extremely easy to isolate the stem cells from the adipose tissue via minimal manipulation or enzymatic digestion of fat [13, 14]. ...
... The improved pulmonary and other organs function after MSC infusions in the study of Zhao's group [1], can be attributed both to immune-modulatory that also to the anti-inflammatory MSCs effects, as these cells release many paracrine factors, which interact with immune cells resulting in immunomodulation, and with inflammation decrease [5, 6, 31]. These effects were confirmed by the increased peripheral lymphocytes amount, the decline in the C-reactive protein, and waning of over-activated cytokine-secreting immune cells (CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells) into the blood of treated patients, by mean 4.5 days later the intravenous infusion [1]. Moreover, 10 x RNA-sequencing analysis displayed that infused MSCs were negative for ACE2 and TMPRSS2, which confirmed that these cells were free from COVID-19 infection. The possible implications of MSCs as anti-viral therapy have been cited by also the Kyoto Encyclopedia of Genes and Genomes (KEGG) [1]. ...
The exciting prospects of new therapies with mesenchymal stromal cells
1
2017
... The improved pulmonary and other organs function after MSC infusions in the study of Zhao's group [1], can be attributed both to immune-modulatory that also to the anti-inflammatory MSCs effects, as these cells release many paracrine factors, which interact with immune cells resulting in immunomodulation, and with inflammation decrease [5, 6, 31]. These effects were confirmed by the increased peripheral lymphocytes amount, the decline in the C-reactive protein, and waning of over-activated cytokine-secreting immune cells (CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells) into the blood of treated patients, by mean 4.5 days later the intravenous infusion [1]. Moreover, 10 x RNA-sequencing analysis displayed that infused MSCs were negative for ACE2 and TMPRSS2, which confirmed that these cells were free from COVID-19 infection. The possible implications of MSCs as anti-viral therapy have been cited by also the Kyoto Encyclopedia of Genes and Genomes (KEGG) [1]. ...
Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study
0
2012
Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial
1
2015
... MSCs have been used extensively in cellular therapies, including both pre-clinical and clinical studies [5-8], suggesting their safety and efficacy. The sources of MSCs are principally two: adipose tissue, and bone marrow [9]. Recent studies introduced a new, interesting, and alternative sources of MSCs represented by Dental Pulp Stem Cells (DPSCs) [10], Periodontal Ligament stem cells (PDLSCs) [11], and Oral Stem Cells [12]. The sub-cutaneous adipose tissue offers a significant edge over other sources because it is easily accessible posing the least amount of discomfort to the patient and being easy to use with local anesthesia. Additionally, it is extremely easy to isolate the stem cells from the adipose tissue via minimal manipulation or enzymatic digestion of fat [13, 14]. ...
Characteristics and Potentiality of Human Adipose-Derived Stem Cells (hASCs) Obtained from Enzymatic Digestion of Fat Graft
4
2019
... MSCs have been used extensively in cellular therapies, including both pre-clinical and clinical studies [5-8], suggesting their safety and efficacy. The sources of MSCs are principally two: adipose tissue, and bone marrow [9]. Recent studies introduced a new, interesting, and alternative sources of MSCs represented by Dental Pulp Stem Cells (DPSCs) [10], Periodontal Ligament stem cells (PDLSCs) [11], and Oral Stem Cells [12]. The sub-cutaneous adipose tissue offers a significant edge over other sources because it is easily accessible posing the least amount of discomfort to the patient and being easy to use with local anesthesia. Additionally, it is extremely easy to isolate the stem cells from the adipose tissue via minimal manipulation or enzymatic digestion of fat [13, 14]. ...
... Minimal manipulation is based on fat mechanical centrifugation and/or filtration, while enzymatic digestion on collagenases uses, as previously described [9, 15-21]. A difference in terms of stem cell amount was reported between procedures [9, 15-21]. ...
... ]. A difference in terms of stem cell amount was reported between procedures [9, 15-21]. ...
... A higher quantity of stem cells was observed in adipose tissue compared to bone marrow [22]. MSCs are multi-potent cells that renew on their own, having the capacity to split into cells of mesenchymal origin in vitro as chondrocytes, adipocytes, and osteoblasts. Human ASCs express the classical mesenchymal markers such as CD44, CD73, CD90, CD105 and CD166 [9], and are located in Stromal Vascular Fraction (SVF) portion of sub-cutaneous fat [23]. For these reasons, it is possible to identify the ASCs as the most important representative of MSCs. ...
Curcumin/Liposome Nanotechnology as Delivery Platform for Anti-inflammatory Activities via NFkB/ERK/pERK Pathway in Human Dental Pulp Treated With 2-HydroxyEthyl MethAcrylate (HEMA)
1
2019
... MSCs have been used extensively in cellular therapies, including both pre-clinical and clinical studies [5-8], suggesting their safety and efficacy. The sources of MSCs are principally two: adipose tissue, and bone marrow [9]. Recent studies introduced a new, interesting, and alternative sources of MSCs represented by Dental Pulp Stem Cells (DPSCs) [10], Periodontal Ligament stem cells (PDLSCs) [11], and Oral Stem Cells [12]. The sub-cutaneous adipose tissue offers a significant edge over other sources because it is easily accessible posing the least amount of discomfort to the patient and being easy to use with local anesthesia. Additionally, it is extremely easy to isolate the stem cells from the adipose tissue via minimal manipulation or enzymatic digestion of fat [13, 14]. ...
Periodontal Ligament Stem Cells: Current Knowledge and Future Perspectives
1
2019
... MSCs have been used extensively in cellular therapies, including both pre-clinical and clinical studies [5-8], suggesting their safety and efficacy. The sources of MSCs are principally two: adipose tissue, and bone marrow [9]. Recent studies introduced a new, interesting, and alternative sources of MSCs represented by Dental Pulp Stem Cells (DPSCs) [10], Periodontal Ligament stem cells (PDLSCs) [11], and Oral Stem Cells [12]. The sub-cutaneous adipose tissue offers a significant edge over other sources because it is easily accessible posing the least amount of discomfort to the patient and being easy to use with local anesthesia. Additionally, it is extremely easy to isolate the stem cells from the adipose tissue via minimal manipulation or enzymatic digestion of fat [13, 14]. ...
Human Oral Stem Cells, Biomaterials and Extracellular Vesicles: A Promising Tool in Bone Tissue Repair
1
2019
... MSCs have been used extensively in cellular therapies, including both pre-clinical and clinical studies [5-8], suggesting their safety and efficacy. The sources of MSCs are principally two: adipose tissue, and bone marrow [9]. Recent studies introduced a new, interesting, and alternative sources of MSCs represented by Dental Pulp Stem Cells (DPSCs) [10], Periodontal Ligament stem cells (PDLSCs) [11], and Oral Stem Cells [12]. The sub-cutaneous adipose tissue offers a significant edge over other sources because it is easily accessible posing the least amount of discomfort to the patient and being easy to use with local anesthesia. Additionally, it is extremely easy to isolate the stem cells from the adipose tissue via minimal manipulation or enzymatic digestion of fat [13, 14]. ...
Plasticity of adipose tissue: A promising therapeutic avenue in the treatment of cardiovascular and blood diseases?
1
2005
... MSCs have been used extensively in cellular therapies, including both pre-clinical and clinical studies [5-8], suggesting their safety and efficacy. The sources of MSCs are principally two: adipose tissue, and bone marrow [9]. Recent studies introduced a new, interesting, and alternative sources of MSCs represented by Dental Pulp Stem Cells (DPSCs) [10], Periodontal Ligament stem cells (PDLSCs) [11], and Oral Stem Cells [12]. The sub-cutaneous adipose tissue offers a significant edge over other sources because it is easily accessible posing the least amount of discomfort to the patient and being easy to use with local anesthesia. Additionally, it is extremely easy to isolate the stem cells from the adipose tissue via minimal manipulation or enzymatic digestion of fat [13, 14]. ...
Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure
1
2006
... MSCs have been used extensively in cellular therapies, including both pre-clinical and clinical studies [5-8], suggesting their safety and efficacy. The sources of MSCs are principally two: adipose tissue, and bone marrow [9]. Recent studies introduced a new, interesting, and alternative sources of MSCs represented by Dental Pulp Stem Cells (DPSCs) [10], Periodontal Ligament stem cells (PDLSCs) [11], and Oral Stem Cells [12]. The sub-cutaneous adipose tissue offers a significant edge over other sources because it is easily accessible posing the least amount of discomfort to the patient and being easy to use with local anesthesia. Additionally, it is extremely easy to isolate the stem cells from the adipose tissue via minimal manipulation or enzymatic digestion of fat [13, 14]. ...
A comparative translational study: the combined use of enhanced stromal vascular fraction and platelet-rich plasma improves fat grafting maintenance in breast reconstruction
4
2012
... Minimal manipulation is based on fat mechanical centrifugation and/or filtration, while enzymatic digestion on collagenases uses, as previously described [9, 15-21]. A difference in terms of stem cell amount was reported between procedures [9, 15-21]. ...
... , 15-21]. ...
... The adipose-derived MSCs, as ASCs and SVFs in which they are contained (1mL of fat tissue offers 100.000 SVFs of which 1% - 3% are ASCs = 1.000/3.000), can be collected by 100mL of fat tissue, obtained by a very simple, fast and safe gently liposuction, performed also in local anesthesia, from the abdomen, flank and thighs regions [15-17, 20]. ...
... With 100mL of processed fat via minimal manipulation, it is possible to obtain an average of 1 × 107 SVFs containing ASCs [15-18]. ...
Breast Reconstruction with Enhanced Stromal Vascular Fraction Fat Grafting: What Is the Best Method?
1
2015
... MSCs and ASCs with related SVF portion have been used in the immune-mediated inflammatory diseases (graft-versus-host disease and systemic lupus erythematosus) [24, 25], in lower extremity ulcers [26], calvarial defects [27], craniofacial microsomia [28], breast reconstruction [16-19, 29, 30], outcomes of burns and scars [20] with safe and interesting results. ...
Engineered Fat Graft Enhanced with Adipose-Derived Stromal Vascular Fraction Cells for Regenerative Medicine: Clinical, Histological and Instrumental Evaluation in Breast Reconstruction
4
2019
... As briefly introduced, SVF contains a larger cellular population, represented by ASCs and Stromal vascular Fraction Cells (SVFs). SVFs and ASCs secrete pro-angiogenic factors, such as Vascular Endothelial Growth Factor (VEGF), platelet-derived growth factors (PDGF), inducing proliferation of endothelial cells, promoting the vascularization, providing physical Extracellular Matrix (ECM) guidance cues that promote endothelial sprouting [17, 18]. Moreover, SVFs and ASCs have immune-modulating proprieties mediated by transforming growth factor-1 (TGF-1), hepatocyte growth factors (HGF) and interferon-γ (INF-γ) [17, 18]. These activities and the early establishment of new micro-capillary networks, which deliver the proper nutrients and oxygen, might contributed to the improved outcomes observed during MSCs infusion in Covid-19 patients. ...
... ]. Moreover, SVFs and ASCs have immune-modulating proprieties mediated by transforming growth factor-1 (TGF-1), hepatocyte growth factors (HGF) and interferon-γ (INF-γ) [17, 18]. These activities and the early establishment of new micro-capillary networks, which deliver the proper nutrients and oxygen, might contributed to the improved outcomes observed during MSCs infusion in Covid-19 patients. ...
... The adipose-derived MSCs, as ASCs and SVFs in which they are contained (1mL of fat tissue offers 100.000 SVFs of which 1% - 3% are ASCs = 1.000/3.000), can be collected by 100mL of fat tissue, obtained by a very simple, fast and safe gently liposuction, performed also in local anesthesia, from the abdomen, flank and thighs regions [15-17, 20]. ...
... All these procedures of fat tissue manipulation, aimed to obtain an SVFs pellet containing ASCs, are regulated by the European rules (1394/2007 EC) and EMA/CAT recommendations (20 June 2014 EMA/CAT/600280/ 2010 Rev 1) [17, 18, 21]. ...
Concise Review: Adipose-Derived Stem Cells (ASCs) and Adipocyte-Secreted Exosomal microRNA (A-SE-miR) Modulate Cancer Growth and promote Wound Repair
6
2019
... As briefly introduced, SVF contains a larger cellular population, represented by ASCs and Stromal vascular Fraction Cells (SVFs). SVFs and ASCs secrete pro-angiogenic factors, such as Vascular Endothelial Growth Factor (VEGF), platelet-derived growth factors (PDGF), inducing proliferation of endothelial cells, promoting the vascularization, providing physical Extracellular Matrix (ECM) guidance cues that promote endothelial sprouting [17, 18]. Moreover, SVFs and ASCs have immune-modulating proprieties mediated by transforming growth factor-1 (TGF-1), hepatocyte growth factors (HGF) and interferon-γ (INF-γ) [17, 18]. These activities and the early establishment of new micro-capillary networks, which deliver the proper nutrients and oxygen, might contributed to the improved outcomes observed during MSCs infusion in Covid-19 patients. ...
... , 18]. These activities and the early establishment of new micro-capillary networks, which deliver the proper nutrients and oxygen, might contributed to the improved outcomes observed during MSCs infusion in Covid-19 patients. ...
... The high secretory activity makes also SVFs and ASCs, as MSCs, a potentially suitable vehicle for the delivery of drugs molecules in the cellular microenvironment, with the potential aim to regenerate damaged tissue as for to nanotechnologies, drug-loaded exosomes, and micro-RNAs (MiRs) [18]. Several MiRs are present in fat, actively participating in the adipogenesis regulation, adipokine secretion, inflammation, and inter-cellular communications in the tissues. These results provide important insights into Adipocyte-secreted exosomal microRNAs (A-Se-MiRs) function and they suggest evaluating the potential role of A-Se-MiRs in human organs and tissue regeneration [18]. In particular, the situation produced by the COVID-19 in currently April, 2020 as pandemic, in which there is not actually any therapy, any vaccines, must push reflect about the idea that may be necessary resort to our SVFs and ASCs and related MiRs for the cure of human pathologies or organ damages. ...
... ]. Several MiRs are present in fat, actively participating in the adipogenesis regulation, adipokine secretion, inflammation, and inter-cellular communications in the tissues. These results provide important insights into Adipocyte-secreted exosomal microRNAs (A-Se-MiRs) function and they suggest evaluating the potential role of A-Se-MiRs in human organs and tissue regeneration [18]. In particular, the situation produced by the COVID-19 in currently April, 2020 as pandemic, in which there is not actually any therapy, any vaccines, must push reflect about the idea that may be necessary resort to our SVFs and ASCs and related MiRs for the cure of human pathologies or organ damages. ...
... With 100mL of processed fat via minimal manipulation, it is possible to obtain an average of 1 × 107 SVFs containing ASCs [15-18]. ...
... All these procedures of fat tissue manipulation, aimed to obtain an SVFs pellet containing ASCs, are regulated by the European rules (1394/2007 EC) and EMA/CAT recommendations (20 June 2014 EMA/CAT/600280/ 2010 Rev 1) [17, 18, 21]. ...
Leptin, adipocytes and breast cancer: Focus on inflammation and anti-tumor immunity
1
2015
... MSCs and ASCs with related SVF portion have been used in the immune-mediated inflammatory diseases (graft-versus-host disease and systemic lupus erythematosus) [24, 25], in lower extremity ulcers [26], calvarial defects [27], craniofacial microsomia [28], breast reconstruction [16-19, 29, 30], outcomes of burns and scars [20] with safe and interesting results. ...
Adipose-derived stromal vascular fraction cells and platelet-rich plasma: basic and clinical evaluation for cell-based therapies in patients with scars on the face
3
2014
... MSCs and ASCs with related SVF portion have been used in the immune-mediated inflammatory diseases (graft-versus-host disease and systemic lupus erythematosus) [24, 25], in lower extremity ulcers [26], calvarial defects [27], craniofacial microsomia [28], breast reconstruction [16-19, 29, 30], outcomes of burns and scars [20] with safe and interesting results. ...
... The adipose-derived MSCs, as ASCs and SVFs in which they are contained (1mL of fat tissue offers 100.000 SVFs of which 1% - 3% are ASCs = 1.000/3.000), can be collected by 100mL of fat tissue, obtained by a very simple, fast and safe gently liposuction, performed also in local anesthesia, from the abdomen, flank and thighs regions [15-17, 20]. ...
... From adipose tissue, by manual extraction, it was obtained approximately 250,000 ± 34,782 nucleated SVFs cells per each mL of fat tissue; on the other hand, by the automatic extractor, the cell yield was approximately 50,000 ± 6,956 nucleated SVFs cells per ml of fat tissue (p < 0.01) [20]. In the first case, 25 × 106 (25.000.000) nucleated SVFs cells can be obtained by 100mL of fat tissue, and 300mL of fat (average 150-400mL) would be the right amount to obtain average 75 × 106 75,000,000 cells. ...
Impact of the Different Preparation Methods to Obtain Human Adipose-Derived Stromal Vascular Fraction Cells (AD-SVFs) and Human Adipose-Derived Mesenchymal Stem Cells (AD-MSCs): Enzymatic Digestion Versus Mechanical Centrifugation
3
2019
... Minimal manipulation is based on fat mechanical centrifugation and/or filtration, while enzymatic digestion on collagenases uses, as previously described [9, 15-21]. A difference in terms of stem cell amount was reported between procedures [9, 15-21]. ...
... -21]. ...
... All these procedures of fat tissue manipulation, aimed to obtain an SVFs pellet containing ASCs, are regulated by the European rules (1394/2007 EC) and EMA/CAT recommendations (20 June 2014 EMA/CAT/600280/ 2010 Rev 1) [17, 18, 21]. ...
Comparing mesenchymal stromal cells from different human tissues: Bone marrow, adipose tissue and umbilical cord blood
1
2008
... A higher quantity of stem cells was observed in adipose tissue compared to bone marrow [22]. MSCs are multi-potent cells that renew on their own, having the capacity to split into cells of mesenchymal origin in vitro as chondrocytes, adipocytes, and osteoblasts. Human ASCs express the classical mesenchymal markers such as CD44, CD73, CD90, CD105 and CD166 [9], and are located in Stromal Vascular Fraction (SVF) portion of sub-cutaneous fat [23]. For these reasons, it is possible to identify the ASCs as the most important representative of MSCs. ...
Functional studies of mesenchymal stem cells derived from adult human adipose tissue. Exp
1
2005
... A higher quantity of stem cells was observed in adipose tissue compared to bone marrow [22]. MSCs are multi-potent cells that renew on their own, having the capacity to split into cells of mesenchymal origin in vitro as chondrocytes, adipocytes, and osteoblasts. Human ASCs express the classical mesenchymal markers such as CD44, CD73, CD90, CD105 and CD166 [9], and are located in Stromal Vascular Fraction (SVF) portion of sub-cutaneous fat [23]. For these reasons, it is possible to identify the ASCs as the most important representative of MSCs. ...
Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis
1
2016
... MSCs and ASCs with related SVF portion have been used in the immune-mediated inflammatory diseases (graft-versus-host disease and systemic lupus erythematosus) [24, 25], in lower extremity ulcers [26], calvarial defects [27], craniofacial microsomia [28], breast reconstruction [16-19, 29, 30], outcomes of burns and scars [20] with safe and interesting results. ...
CT-04 Safety and efficacy of allogeneic umbilical cord-derived mesenchymal stem cells (MSCs) in patients with systemic lupus erythematosus: results of an open-label phase I study
1
2018
... MSCs and ASCs with related SVF portion have been used in the immune-mediated inflammatory diseases (graft-versus-host disease and systemic lupus erythematosus) [24, 25], in lower extremity ulcers [26], calvarial defects [27], craniofacial microsomia [28], breast reconstruction [16-19, 29, 30], outcomes of burns and scars [20] with safe and interesting results. ...
Application of enhanced stromal vascular fraction and fat grafting mixed with PRP in post-traumatic lower extremity ulcers
1
2011
... MSCs and ASCs with related SVF portion have been used in the immune-mediated inflammatory diseases (graft-versus-host disease and systemic lupus erythematosus) [24, 25], in lower extremity ulcers [26], calvarial defects [27], craniofacial microsomia [28], breast reconstruction [16-19, 29, 30], outcomes of burns and scars [20] with safe and interesting results. ...
Autologous stem cells (adipose) and fibrin glue used to treat widespread traumatic calvarial defects: case report
1
2004
... MSCs and ASCs with related SVF portion have been used in the immune-mediated inflammatory diseases (graft-versus-host disease and systemic lupus erythematosus) [24, 25], in lower extremity ulcers [26], calvarial defects [27], craniofacial microsomia [28], breast reconstruction [16-19, 29, 30], outcomes of burns and scars [20] with safe and interesting results. ...
Fat graft supplemented with adipose-derived stromal cells in the rehabilitation of patients with craniofacial microsomia
1
2013
... MSCs and ASCs with related SVF portion have been used in the immune-mediated inflammatory diseases (graft-versus-host disease and systemic lupus erythematosus) [24, 25], in lower extremity ulcers [26], calvarial defects [27], craniofacial microsomia [28], breast reconstruction [16-19, 29, 30], outcomes of burns and scars [20] with safe and interesting results. ...
Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells
1
2007
... MSCs and ASCs with related SVF portion have been used in the immune-mediated inflammatory diseases (graft-versus-host disease and systemic lupus erythematosus) [24, 25], in lower extremity ulcers [26], calvarial defects [27], craniofacial microsomia [28], breast reconstruction [16-19, 29, 30], outcomes of burns and scars [20] with safe and interesting results. ...
Prospective trial of adipose-derived regenerative cell (ADRC)-enriched fat grafting for partial mastectomy defects: the RESTORE-2 trial
1
2012
... MSCs and ASCs with related SVF portion have been used in the immune-mediated inflammatory diseases (graft-versus-host disease and systemic lupus erythematosus) [24, 25], in lower extremity ulcers [26], calvarial defects [27], craniofacial microsomia [28], breast reconstruction [16-19, 29, 30], outcomes of burns and scars [20] with safe and interesting results. ...
Covid-19 - Navigating the uncharted
1
2020
... The improved pulmonary and other organs function after MSC infusions in the study of Zhao's group [1], can be attributed both to immune-modulatory that also to the anti-inflammatory MSCs effects, as these cells release many paracrine factors, which interact with immune cells resulting in immunomodulation, and with inflammation decrease [5, 6, 31]. These effects were confirmed by the increased peripheral lymphocytes amount, the decline in the C-reactive protein, and waning of over-activated cytokine-secreting immune cells (CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells) into the blood of treated patients, by mean 4.5 days later the intravenous infusion [1]. Moreover, 10 x RNA-sequencing analysis displayed that infused MSCs were negative for ACE2 and TMPRSS2, which confirmed that these cells were free from COVID-19 infection. The possible implications of MSCs as anti-viral therapy have been cited by also the Kyoto Encyclopedia of Genes and Genomes (KEGG) [1]. ...