key: cord-0966546-errpfmcj
authors: Kirkham, Aidan M.; Monaghan, Madeline; Bailey, Adrian J.M.; Shorr, Risa; Lalu, Manoj M.; Fergusson, Dean A.; Allan, David S.
title: Mesenchymal stem/stromal cell-based therapies for COVID-19: First iteration of a living systematic review and meta-analysis: MSCs and COVID-19
date: 2022-01-31
journal: Cytotherapy
DOI: 10.1016/j.jcyt.2021.12.001
sha: a81816b2960730b27e7f4371a69d212c2c590001
doc_id: 966546
cord_uid: errpfmcj

BACKGROUND: : Mesenchymal stem/stromal cells (MSCs) and their secreted products are a promising therapy for COVID-19 given their immunomodulatory and tissue repair capabilities. Many small studies were launched at the onset of the pandemic and repeated meta-analysis is critical to obtain timely and sufficient statistical power to determine efficacy. METHODS AND FINDINGS: : All English language published studies identified in our systematic search (up to February 3, 2021) examining the use of MSC-derived products to treat patients with COVID-19 were identified. Risk of bias (RoB) was assessed for all studies. Nine studies were identified (189 patients) and four were controlled (93 patients). Three of the controlled studies reported on mortality (primary analysis) and were pooled through random effects meta-analysis. MSCs decreased the risk of death at study endpoint compared to controls (RR: 0.18, 0.04-0.74; p=0.02; I(2)=0%) although follow-up differed. Among secondary outcomes, IL-6 levels were most commonly reported and were decreased compared to controls (SMD: -0.69, -1.15 to -0.22, p=0.004; I(2)=0%) (n=3 studies). Other outcomes were not reported consistently and pooled estimates of effect were not performed. Substantial heterogeneity was observed between studies in terms of study design. Adherence to published ISCT criteria for MSC characterization was low (2 of 9 studies RoB analysis revealed a low to moderate risk of bias in controlled studies and uncontrolled case series were of good (3 studies) or fair (2 studies) quality. CONCLUSION: : Use of MSCs to treat COVID-19 appears promising, however, few studies were identified and potential risk of bias was detected in all studies. More controlled studies that report uniform clinical outcomes and use MSC products that meet standard ISCT criteria should be performed. Future iterations of our systematic search should refine estimates of efficacy and clarify potential adverse effects.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogenic betacoronavirus that causes coronavirus disease 2019 (COVID-19), has spread rapidly around the world, creating an urgent need for effective therapies that can prevent excessive mortality (1) .

SARS-CoV-2 infects cells via attachment of its spike (S) protein to the angiotensin converting enzyme 2 (ACE2) receptor on the surface of target cells (2) . The subsequent endocytosis of the ACE2 complex leads to increased free serum Angiotensin II (Ang II) which can induce profound inflammatory responses through binding with angiotensin receptor type 1 and activation of nuclear factor kappa-light chain enhancer of activated B cells (NF-kB) pathway (3) and the conversion of membrane bound IL-6Rα to soluble IL-6 (sIL-6), activating signal transducer and activator of transcription 3 (STAT3) (3) . The synergistic activation of NF-kB and STAT3 creates a positive feedback loop that further augments the production of pro-inflammatory cytokines and chemokines (3), attracting pro-inflammatory immune cells to infected tissues (4) and resulting in a dramatic augmentation in pro-inflammatory cytokine production termed the "cytokine storm" (5) . This cytokine storm causes considerable tissue damage through apoptosis, necroptosis (6) and pyroptosis (7) . Pro-inflammatory responses and the cytokine storm induced by SARS-CoV-2 infection can lead to pulmonary complications including acute lung injury, pulmonary edema and acute respiratory distress syndrome (ARDS) (8, 9) which may require intubation and ventilator support in intensive care units.

Since SARS-CoV-2 first emerged in December 2019, few approved therapies have emerged to supplement the ongoing COVID-19 vaccination efforts that have been launched (10) .

With many people remaining vulnerable due to slower uptake of vaccinations in some areas, combined with the emergence of increasing variants of concern, the need for effective therapy remains a pressing issue.

Mesenchymal stem/stromal cells (MSCs) were quickly viewed with significant promise to treat COVID-19 (11) and many studies were launched rapidly with several now completed and reported. MSCs are multipotent stem like cells which can be isolated from a number of adult and neonatal tissues including bone marrow, adipose, umbilical cord and placenta among the others (12) . MSCs Living systematic reviews are an emerging method of conducting systematic reviews which involves frequent updating to incorporate new evidence as soon as it becomes available, providing clinicians, scientists and policymakers with the most up to date high quality information surrounding specific topics (27) . Living systematic reviews have been recently conducted to provide estimates regarding the safety and efficacy for many re-purposed therapeutics in the context of COVID-19 (28-30) and seems most appropriate for the analysis of MSCs in COVID-19 due to the expectation that many studies were launched early in the pandemic and will be published over the next 12 to 18 months (31).

Pooled estimates regarding the use of MSCs to treat patients with COVID-19 are needed as nearly all studies in this area are small and lack sufficient statistical power to determine efficacy on their own. Meta-analysis may be limited, however, by heterogeneity in aspects of study design, product characterization, outcome measures and differences in participant populations enrolled between studies. Timely regulatory approval and clinical translation will likely require meta-analysis of similar high quality well-designed studies identified through a systematic search of the literature to determine whether MSC-based therapeutics are safe and effective for the treatment of COVID-19. A living systematic review and meta-analysis is needed to keep pace with the rapid evolution of new information related to the pandemic and to provide insight from a combined sample size that will have sufficient power for determining efficacy.

This systematic review is reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines (32) (Table S4. ). The study protocol has been published (33) and is registered at the International Prospective Registry of Systematic Reviews (PROSPERO; CRD42021225431).

A systematic search of all clinical studies (controlled and uncontrolled) examining the use of MSCs and/or their secretome (which includes conditioned media (MSC-CM), or extracellular vesicles (MSC-EVs) derived from MSCs) as a therapeutic intervention was conducted from 1947 to February 3, 2021 in Embase Classic+Embase, Ovid MEDLINE(R), Ovid EBM Reviews and the Cochrane Central Register of Controlled Trials. The search strategy was developed in collaboration with a health sciences librarian (RS) specializing in systematic review searches and was peer reviewed by a second librarian according to the Peer Review of Electronic Search Strategies (PRESS) framework (34). The reference lists of included studies and relevant reviews captured by the search were also examined by two independent reviewers (AMK, MM) to ensure that all relevant articles were captured. The full search strategy is outlined in Figure S1 .

All English-language, full-text, clinical studies examining the use of MSCs or their secretome (MSC-EVs, MSC-CM) as a therapeutic intervention for COVID-19 were included. Studies could be single armed (uncontrolled) or have a comparator or control groups (controlled). For the controlled studies, all randomization methods were considered acceptable (randomized, pseudorandomized, and non-randomized). Studies published in languages other than English, review articles, commentaries, editorials, letters, case reports, conference abstracts, unpublished gray literature and other study types (in vitro studies, preclinical animal studies, etc.) were excluded.

All symptomatic or asymptomatic patients with confirmed SARS-CoV-2 infection (qRT-PCR, antibody assay, etc) were included. MSCs derived from any know applicable tissue source (bone marrow, adipose, umbilical cord, dental pulp, placenta etc.) were acceptable. MSCs could be obtained from syngeneic, allogeneic or xenogeneic tissues. All routes of MSC/secretome administration were acceptable (intravenous injection, aerosol inhalation, intramuscular injection, etc). MSC-based products could also be administered along with other therapeutic agents (antivirals, anti-cytokine drugs, immunomodulatory agents, etc.). Studies exclusively investigating other non-MSC based therapeutics were excluded.

The primary analysis of this study was mortality rate at study endpoint. Secondary analyses included number of patients requiring hospitalization, number of patients requiring intensive care unit (ICU) admission, number of patients requiring mechanical ventilation, length of time in hospital, length of time in ICU, length of time on mechanical ventilation, presence and severity of clinical symptoms (fever, cough, shortness of breath, chest pain, etc), presence and size of pulmonary lesions on radiographic imaging (ie. CT scan) and change in oxygenation levels (e.g.

PaO2/FiO2 ratio), viral load, body temperature, organ failure assessment score (e.g. SOFA), circulating levels of immune cells (lymphocytes, neutrophils, macrophages, regulatory dendritic cells, NK cells), pro-inflammatory cytokines, (IL-6, TNF-α, IFN-γ, etc.), anti-inflammatory cytokines (IL-10, TGF-β, etc.) and inflammatory markers (C-reactive protein, Ferritin, D-dimer, etc.), and adverse events arising from MSC-based product administration (tumorigenesis, thromboembolism, etc.)

All citations identified in the search were imported into Rayyan, (https:// rayyan.qcri.org/) for management of search records. After duplicates were removed, the study titles and abstracts were screened in duplicate by two independent reviewers (AMK, MM). After all potentially relevant titles and abstracts were identified, the full texts of all potentially relevant studies were reviewed in duplicate to determine final eligibility. In cases of disagreement between the two reviewers, consensus was achieved through discussion with a third senior team member (DSA).

All relevant data was extracted in duplicate by two independent reviewers (AK, MM) from the included studies using a standardized data extraction template in Microsoft Excel (Microsoft, Seattle, USA). In cases of disagreement between the two reviewers, the differences were RoB assessment was conducted using the Risk-of-Bias Tool for Randomized Trials (ROB 2) tool (37) for randomized controlled trials, the Risk of Bias In Non-randomized Studies of Interventions (ROBINS I tool) (38) for non-randomized controlled studies, and the Evidence Based Medicine (EBM) tool (39) for case series. Image J software was used to extract data in graphical format (https://imagej.nih.gov/ij/download.html).

The results from individual studies were pooled for meta-analysis using Review Manager (Version 5.4) Systematic Review Software (https://training.cochrane.org/online-learning/coresoftware-cochrane-reviews/revman/revman-5-download). For dichotomous outcomes, risk ratios (RRs) were calculated to determine the risk of death between the control and experimental groups at study endpoint. For continuous outcomes, the standardized mean difference (SMD) between control and experimental groups was calculated using random effects meta-analyses.

Significance in pooled analysis was performed using the DerSimonian and Laird random effects model. All data is presented with 95% confidence intervals (CIs). Meta-analysis was only performed when three or more controlled studies reported on the same outcome. Outcomes that were reported in less than three controlled studies or where adequate data for inclusion in metaanalysis was not provided were analyzed in a descriptive manner. Statistical heterogeneity was assessed using the I 2 statistic. Potential subgroup analyses were determined a priori in our study protocol with the goal of determining if the effect of MSCs as a therapeutic intervention for COVID-19 was significantly different for studies that used MSCs from specific tissue sources, MSCs vs secreted factors (MSC-EVs, MSC-CM), or in patients with varying COVID-19 severity. Due to the small number of studies included in each of our quantitative analyses, we did not perform a planned analysis for publication bias. Finally, p<0.05 was considered significant for all analyses.

A total of 459 unique records were identified in our systematic search of the literature after duplicates were removed. Nine articles met the criteria for inclusion in our analysis (40-48).

Reasons for study exclusion were trial protocol only (n=57), reviews, editorials or commentaries (n=9), non-MSC cells (n=8), and uncontrolled case series in languages other than English (n=4; Spanish (n=1), Chinese (n=1), Persian (n=1), and Russian (n=1)). (Figure 3 )

The characteristics of the 9 included studies are summarized in Table 1 

In total, there were 189 patients (mean age 58.3 ± 6.3; 124 male) enrolled across all study groups and 136 patients (mean age 58.5 ± 6.7; 96 male) were administered MSC-based therapy as a therapeutic intervention for COVID-19. In the controlled studies, 40 patients (55.5 ± 7.1 years of age; 24 male) were treated with MSCs and 53 patients (57.9 ± 6.4 years of age; 28 male) served as controls. The distribution of patients with mild, moderate, severe, and critical COVID-19 at the time of treatment with MSC-based treatment was somewhat similar for patients in the intervention groups and controls, however, there were more patients with mild COVID-19 and fewer with severe disease in the intervention group compared to the control group (Table 1 ).

In terms of patient co-morbidities, there were more obese patients in the intervention group compared to controls (27.5% vs 9.4%). However, all other co-morbidities including hypertension, diabetes, chronic obstructive pulmonary disease (COPD), coronary artery disease and hyperlipidemia appeared well balanced between control and intervention groups. (Table 1 ).

Intervention characteristics are summarized in Table 2 . Eight studies used MSCs (40-43,45-48) and one study used MSC-EVs (exosomes) (44). All MSCs were derived from allogeneic human tissues, including umbilical cord (n=5) (41-43,45,46), bone marrow (n=1) (44) and adipose tissue (n=1) (47). One study used MSCs derived from both umbilical cord and placental tissue (48).

One study did not report the tissue source from which its MSCs were obtained (40). The passage number of the MSCs varied widely between studies (see Table 2 ), with four studies not reporting how many passages were performed before harvesting MSCs from ex vivo culture. With regards to the extent that studies reported on specific ISCT criteria (35) for MSC characterization, only two of the nine studies addressed all three minimal criteria established by the ISCT. Specific details regarding the number of studies meeting each of the three individual ISCT criteria can be found in Table 2 . The study that used MSC-EVs (termed "exosomes" in the study) did not report Table 2 ). The reported time from COVID-19 diagnosis to MSC administration (median of 6.5 days across studies (n=8), range 1-15 days) was similar between control groups (4.0, range 1 -14) and intervention groups (5.9, range 1 -11.5) in the controlled studies.

Patients were administered other therapeutic agents in addition to MSCs or MSC-EVs in eight of the nine studies (88%). The specific therapeutic agents administered varied considerably between studies and are summarized in Table 2 . Two of the studies stated that they used medications in addition to MSCs but did not specify which medications were used. The median period of follow up after MSC administration was 22.0 days (range 14-60 days).

Outcomes reported across studies are summarized in Table 3 . All nine studies reported mortality.

The mortality rate at endpoint for all patients administered MSCs or MSC-EVs was 17 of 136 patients (12.5%). In the controlled studies, the mortality rate at endpoint for the combined control groups was 11 of 53 patients (20.7%), whereas the mortality rate for the combined MSC groups was 1 of 40 patients (2.5%). In meta-analysis of the controlled studies (n=3), MSCs were associated with a decreased risk of death at study endpoint (RR: 0.18 [0.04-0.74, 95% CI, p=0.02, I 2 =0%]) compared to the control group ( Figure 4 ). 

Six of the nine studies (3 controlled) reported on the number of patients hospitalized for COVID-19 at the beginning and end of their study periods. All of the 97 patients (100%) who received MSCs or MSC-EVs were hospitalized at time of enrollment and only 32 of 97 patients (33.0%) were still in hospital at the end of the respective study periods. In controlled studies, patients who received MSCs were less likely to remain hospitalized at the end of the study period compared to controls (OR: 0.34 [0.12-0.91, 95% CI, p=0.03]).

All nine studies reported pro-inflammatory cytokines at baseline and study endpoint. Three of the controlled studies reported serum IL-6 levels at study endpoint in a format which could be combined in meta-analysis which revealed that MSCs significantly decreased serum IL-6 levels 

Four studies (2 controlled) reported changes in viral load from baseline to study endpoint. At the beginning of these studies, all the patients administered MSCs (100%) were positive for SARS-CoV-2 viral RNA. At the respective endpoints of these studies, none of the patients administered MSCs (0%) were positive for SARS-CoV-2 viral RNA. Two studies (1 controlled) reported on changes in SARS-CoV-2 antibody titers in patients administered MSCs. Both studies displayed increasing antibody titers from baseline to endpoint in patients treated with MSCs compared to controls.

Adverse events are summarized in Table 4 . Three studies reported adverse events associated with MSC infusion. These adverse events included facial flushing, transient fever, and shivering.

However, these symptoms resolved in all patients spontaneously or with minimal supportive treatment between 1 and 24 hours after MSC administration. Six studies reported no adverse events associated with MSC infusion. None of the studies reported severe adverse events associated with MSC infusion.

Risk of bias (RoB) was assessed for the outcomes of mortality and IL-6 levels in RCTs.

Regarding mortality, one study (43) was found to have low risk of bias while the other RCT (41) had a risk of bias of "some concerns" (Table S1 ) as the method of randomization was unclear and it was unclear whether there were deviations from intended interventions or selection of reported results. Regarding changes in IL-6 levels, one RCT (43) had a low risk of bias while the other RCT (41) had "some concerns" regarding potential risk of bias (Table S2 ) as the method of randomization was unclear and it was unclear whether there were deviations from intended interventions, missing outcome data or selective reporting of results. For non-randomized studies (40,42), both were found to have a moderate risk of bias (Table S3) . Both studies had potential bias due to confounding, measurement of outcomes (as studies did not mention blinding), and selection of reported results (as neither study pre-registered their protocol). Of the included caseseries, three were found to be of good quality (45,47,48) and two of fair quality (44,46) ( Table   S4 ). Two of the case series did not present characterisation of their MSCs (44,46). Lack of uniform outcome reporting across studies limits the ability to easily combine results in meta-analysis and remains problematic for the translation of MSC therapies to more broad clinical use. Marked heterogeneity in MSC-based studies has been previously described for studies addressing graft-versus-host disease that complicates allogeneic hematopoietic cell transplantation (62) . The only two outcome measures, however, that could be combined in metaanalysis were mortality and IL-6 levels. Time points at which mortality and IL-6 levels were measured varied considerably between studies so risk of death and IL-6 levels at study endpoint were used as effect estimates rather than the preferred approach of using a common time point Moreover MSC-EVs have many potential advantages over their parent cells. Firstly, MSC-EVs have favorable storage properties and can be freeze dried and reconstituted quickly for easy storage, transport and rapid administration (67) . Furthermore, MSC-EVs are less prone to host clearance given their reduced immunogenicity compared to their parent MSCs (64, 68, 69) , allowing for greater persistence in recipients. MSC-EVs may also be amenable to a broader range of delivery methods, such as aerosol inhalation, which may be particularly relevant in the context of COVID-19 (64). Although we were unable to perform subgroup analysis to compare the efficacy of MSC-EVs to their parent MSCs in this first edition of our living systematic review, we anticipate that an analysis of this nature will be possible in future updates.

All the studies in our review used third party allogeneic MSCs. One of the reasons why allogeneic MSC therapy is favoured over autologous MSC therapy is that third party allogeneic MSCs can be used in an "off the shelf" manner when needed (65) . In contrast, autologous MSC therapy may introduce marked delays in treatment given the time and resources required to manufacture small batches of personalized autologous MSC products (66, 67) . Allogeneic MSCs can be easily obtained from neonatal tissues such as placental, umbilical cord tissue and amniotic fluid, as well as bone marrow, adipose tissue and other tissues. Furthermore, autologous MSCs from patients with advanced age or underlying health conditions have diminished therapeutic efficacy compared to allogeneic MSCs isolated from healthy donors (68, 69, 70) . One study demonstrated that MSCs isolated from donors with type I diabetes mellitus displayed significant down-regulation of immunomodulatory properties compared to MSCs from healthy individuals (75) . Furthermore, one study showed that adipose tissue derived MSCs from aged donors displayed senescent features along with reduced viability, proliferation and differentiation potential compared to MSCs from young donors (76).

Despite their many advantages, it remains unclear as to whether HLA-matching between donors and recipients is important to achieve maximum safety and therapeutic efficacy (77).

Some studies have shown that allogeneic MSCs may not be as immune privileged as originally thought and may in fact be eliminated through immune-based rejection and/or cause mild allergic reactions or adverse events following in vivo administration in cases of poor HLA matching (78,79). Despite these potential drawbacks, the therapeutic benefits provided by allogeneic MSCs typically outweigh their downsides (71, 74) . This is particularly true in the 

AT-MSCs have more potent immunomodulatory properties and exhibit greater IDO production compared to BM-MSCs (73) . For the treatment of COVID-19 it may be important to select tissue sources that yield MSCs with reduced expression or lack of the ACE2 receptor (74, 75) . This could allow MSCs to persist longer following administration in patients with COVID-19. One report suggested that placenta and pluripotent stem cell-derived MSCs may be optimal for the treatment of COVID-19 given their potent anti-inflammatory activity and low ACE2 expression inclusion of high quality studies is provided that could accelerate future regulatory reviews (see Table 6 ).

Our systematic review and meta-analysis suggests that MSCs are a promising treatment for COVID-19, though the certainty of this effect is limited due to the small number of studies and modest numbers of patients enrolled, as well as substantial heterogeneity between studies in terms of study design, characterization of MSC products, and outcome reporting. IDO, indolamine 2,3-dioxygenase; PGE2, prostaglandin E2; IL, interleukin; IFN-, interferon gamma; TGF-β, transforming growth factor beta; HGF, human growth hormone; NO, nitric oxide; CXCL2, C-X-C chemokine ligand 2; CXCR2, C-X-C receptor 2; Th, T helper type; STAT3, signal transducer and activator of transcription 3; NF-kB, nuclear factor kappa-lightchain enhancer of activated B cells; NRF, nuclear receptor factor; IGFBP-3, insulin-like growth factor binding protein 3 SD, standard deviation *includes ex-smoker, pre-diabetes, asthma Pts -Patients Table 4 . Adverse events (AEs) and severe adverse events (SAEs) reported in clinical studies examining MSCs as a therapeutic intervention for COVID-19. Controlled studies are highlighted in grey. Table 6 . Recommended criteria for performing meta-analysis for purposes of potential regulatory approval of MSC-based therapy for COVID-19.

Number of studies  Sufficient number and similar enough to perform meta-analysis that achieves the required power for determining efficacy. See sample size. Study characteristics  Controlled with contemporary and similar control groups. Randomized is preferable. Concomitant therapies should be controlled.

 To reduce mortality from 10% to 5%, a total sample of size of 686 in the intervention group is needed (24) Study populations  Severe or critical COVID-19 in hospitalized patients is most commonly reported. Outcome measurement  Mortality at day 28 is most commonly reported.  WHO response criteria recommended but not commonly reported.  Secondary: IL6 levels, functional status, hospitalization, ICU admission, pulmonary function at 1, 6, 12 months.  Safety and adverse event reporting in accordance with best practices. Product characterization  MSCs produced and characterized according to GMP practices and ISCT criteria.  MSC-EVs characterized in accordance with MISEV criteria.

 Studies with high risk of potential bias should not be included in meta-analysis.

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