Review Open Access
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Feb 26, 2024; 16(2): 70-88
Published online Feb 26, 2024. doi: 10.4252/wjsc.v16.i2.70
Therapeutic utility of human umbilical cord-derived mesenchymal stem cells-based approaches in pulmonary diseases: Recent advancements and prospects
Min Meng, Wei-Wei Zhang, Shuang-Feng Chen, Chang-Hui Zhou, Department of Central Laboratory, Liaocheng People’s Hospital, Liaocheng 252000, Shandong Province, China
Da-Rui Wang, Department of Clinical Laboratory, Liaocheng People’s Hospital, Liaocheng 252000, Shandong Province, China
ORCID number: Min Meng (0000-0002-3055-7948); Wei-Wei Zhang (0009-0004-5893-4065); Shuang-Feng Chen (0009-0008-8205-9378); Chang-Hui Zhou (0000-0002-9573-7966).
Co-first authors: Min Meng and Wei-Wei Zhang.
Co-corresponding authors: Chang-Hui Zhou and Da-Rui Wang.
Author contributions: Meng M and Zhang WW contributed equally to this work. Meng M and Zhang WW collected the references, analyzed clinical trials, and drafted the manuscript; Zhou CH andChen SF contributed to the conception and design of the review; Zhou CH andWang DR critically and systemically revised the manuscript; and all authors read and approved the final manuscript. Zhou CH andWang DR contributed efforts of equal substance in the research process. The choice of these researchers as co-corresponding authors acknowledges and respects this equal contribution. In summary, we believe that designating Zhou CH andWang DR as co-corresponding authors of is fitting for our manuscript as it accurately reflects our team’s equal contributions, collaborative spirit, and diversity.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Chang-Hui Zhou, MD, Doctor, Department of Central Laboratory, Liaocheng People’s Hospital, No. 67 Dongchang West Road, Liaocheng 252000, Shandong Province, China. zhouchanghui008@163.com
Received: November 30, 2023
Peer-review started: November 30, 2023
First decision: December 17, 2023
Revised: January 4, 2024
Accepted: January 29, 2024
Article in press: January 29, 2024
Published online: February 26, 2024

Abstract

Pulmonary diseases across all ages threaten millions of people and have emerged as one of the major public health issues worldwide. For diverse disease conditions, the currently available approaches are focused on alleviating clinical symptoms and delaying disease progression but have not shown significant therapeutic effects in patients with lung diseases. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) isolated from the human UC have the capacity for self-renewal and multilineage differentiation. Moreover, in recent years, these cells have been demonstrated to have unique advantages in the treatment of lung diseases. We searched the Public Clinical Trial Database and found 55 clinical trials involving UC-MSC therapy for pulmonary diseases, including coronavirus disease 2019, acute respiratory distress syndrome, bronchopulmonary dysplasia, chronic obstructive pulmonary disease, and pulmonary fibrosis. In this review, we summarize the characteristics of these registered clinical trials and relevant published results and explore in depth the challenges and opportunitiesfaced in clinical application. Moreover, the underlying molecular mechanisms involved in UC-MSC-based therapy for pulmonary diseases are also analyzed in depth. In brief, this comprehensive review and detailed analysis of these clinical trials can be expected to provide a scientific reference for future large-scale clinical application.

Key Words: Pulmonary diseases, Mesenchymal stem cells, Human umbilical cord, Cell therapy, Clinical trials

Core Tip: Pulmonary diseases across all ages threaten millions of people and have emerged as one of the major public health issues worldwide. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are superior for standardization and large-scale production for disease treatment. Herein, we provide a detailed summary of clinical trials and results related to the use of UC-MSCs in the treatment of lung diseases and explore in depth the challenges and opportunities faced in the clinical application of these cells.



INTRODUCTION

Pulmonary diseases across all ages are mainly caused by trauma, air pollution, long-term smoking, population aging, and various respiratory virus infections, such as coronavirus disease 2019 (COVID-19), and exert tremendous negative impacts on health status, quality of life, and socioeconomic costs[1,2]. In the last decade, the increasingly high rates of morbidity and mortality due to acute and chronic lung diseases have led to ongoing burdens on public health and health care systems worldwide[3]. According to the systemic analysis for Global Burden of Study 2017, chronic respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension, and occupational diseases, have affected more than 500 million people globally[4]. Acute respiratory distress syndrome (ARDS) is recognized as the most severe form of acute lung injury (ALI) according to the 2012 Berlin definition[5]. ARDS is commonly caused by sepsis, smoke inhalation injury, near-drowning, severe pneumonia, or pulmonary contusion and is present in approximately 10% of all patients in intensive care units worldwide[6,7]. The mortality rate for ARDS patients has remained high, at 30%-40%, in most clinical studies[8,9]. Regardless of the pathophysiology of chronic respiratory disease or ALI, these diverse conditions are usually associated with inflammatory cell infiltration, inflammation-induced disruption of the alveolar epithelial and endothelial barrier, a decrease in alveolar fluid clearance, associated cytokine release, airway inflammation and remodeling, and pulmonary fibrosis development[3]. Currently available therapeutic approaches (e.g.,antibiotic/anti-inflammatory drugs, corticosteroids, specific cytokine inhibitors, bronchodilators, artificial respiratory support, mechanical ventilation, and restricted fluid input) are focused on alleviating clinical symptoms and delaying disease progression[10]. Hence, the development of novel therapeutic approaches for pulmonary diseases is of paramount significance for attenuating immune responses and fostering tissue regeneration.

Mesenchymal stem cells (MSCs) have unique immunomodulatory, regenerative and differentiation properties, and MSC-based therapies have received increasing attention for the treatment of pulmonary diseases, including COVID-19, ALI/ARDS, bronchopulmonary dysplasia (BPD), COPD, IPF and silicosis[11]. MSCs are nonhematopoietic stem cells with multilineage differentiation capacities and can be isolated from bone marrow (BM), umbilical cord (UC), adipose tissue (AT), placenta, peripheral blood (PB), lung, and other tissues[12,13]. Although MSCs have numerous potential therapeutic applications, they can also have detrimental effects depending on the microenvironment, and the tumorigenicity of transplanted MSCs is a current concern that has been well documented through the use of single-cell transcriptomes[14]. In addition, the heterogeneity of MSCs is determined by multiple factors, such as donors, tissue sources, cell populations, culture conditions, cell isolation techniques, and cryoprotective and thawing protocols, and can also lead to inconsistent clinical application efficacy[15]. All these factors, to some extent, constrain the clinical efficacy and application of MSCs. BM-derived MSCs (BM-MSCs) were first discovered and are considered the main source for clinical application; however, they eventually degrade, exhibiting a loss of proliferation and senescence[16]. Among these sources, UC-MSCs have emerged as a promising candidate due to their easy collection, noninvasive isolation methods, rapid proliferation ability, low immunogenicity, few ethical concerns, superior immunological regulation potential and anti-inflammatory effects[17-21]. More importantly, UC-MSCs are superior for standardization and large-scale production for disease treatment. MSCs from these neonatal tissues possess increased proliferative capacity in vitro[22]. Moreover, the number of MSCs obtained from UC specimens is far greater than that obtained from BM or AT and is not limited by donor age, which partially eliminates the impact of cell heterogeneity on clinical treatment and outcome analysis[23,24]. In terms of the therapeutic benefit of UC-MSCs in patients with pulmonary diseases, an increasing number of clinical studies have demonstrated the safety and efficacy of UC-MSCs in regulating the function of immune cells, alleviating the inflammatory response, improving pulmonary function, enhancing lung tissue regeneration and repair, and attenuating lung fibrosis[3]. Therefore, considering these advantages, UC-MSCs are recommended to be considered as appropriate sources of MSCs for the management of pulmonary diseases in both pediatric and adult populations. In this review, we provide a detailed summary of clinical trials and results related to the use of UC-MSCs in the treatment of lung diseases and explore in depth the challenges and opportunities faced in the clinical application of these cells.

UNDERLYING MOLECULAR MECHANISMS OF UC-MSCS IN PULMONARY DISEASES

UC-MSCs are located mainly in the umbilical vein subendothelial, subamnion and perivascular regions and in Wharton’s jelly (WJ); these cells are composed mainly of sponge-like structures woven with collagen fibers, proteoglycans and embedded stromal cells[25,26]. In recent years, there has been enormous progress in understanding the similarities and differences between MSCs derived from various human tissues[27]. Compared to AT-MSCs and BM-MSCs, UC-MSCs are easier to obtain and culture due to the noninvasive collection method used after birth, the ease of in vitro expansion and ethical access[28]. In addition, UC-MSCs exhibit lower immunogenicity, greater proliferation and differentiation potential, a slower senescence rate, and greater anti-inflammatory and immunomodulatory effects than AT-MSCs and BM-MSCs, suggesting that UC-MSCs might be a better alternative for the treatment of pulmonary diseases, especially during the COVID-19 pandemic[13,19-21]. UC-MSCs have shown safety and efficacy in clinical trials for a variety of pulmonary diseases. Furthermore, UC-MSCs have been demonstrated to inhibit inflammation and fibrosis and accelerate the regeneration of functional lung tissue, representing a relatively effective therapy with promising results[29]. The potential mechanisms of action of UC-MSCs in patients with lung-related diseases include immunomodulatory and anti-inflammatory effects, regenerative and differentiation properties, and antimicrobial effects (Figure 1).

Figure 1
Figure 1 Potential mechanisms of umbilical cord-derived mesenchymal stem cells therapy in pulmonary diseases. The therapeutic effects of umbilical cord-derived mesenchymal stem cells in treating pulmonary diseases involve multiple mechanisms, such as the immunomodulatory and anti-inflammatory functions, the regenerative and differentiation properties, and the antimicrobial effects. IL: Interleukin; PGE2: Prostaglandin E2; PD-L1: Programmed cell death protein ligand 1; EVs: Extracellular vesicles; CRP: C-reactive protein; MCP: Monocyte chemoattractant protein; IFN: Interferon; TNF: Tumor necrosis factor; HGF: Hepatocyte growth factor; KGF: Keratinocyte growth factor; MMP: Matrix metalloprotease; TLR: Toll-like receptor; CXCL: C-X-C motif chemokine ligand; TIMP: Tissue inhibitor of matrix metalloproteinase; NK: Natural killer; AEC: Alveolar epithelial cell.

The immunomodulatory and anti-inflammatory properties of UC-MSCs have been extensively studied. The modulation of host innate and adaptive immune responses by UC-MSCs is mediated by direct cell-to-cell contact and paracrine effects. Briefly, the majority of exogenous UC-MSCs can migrate to the injured lung after intratracheal administration and directly interact with immune cells, such as monocytes, macrophages, natural killer (NK) cells, T cells, B cells, and dendritic cells. A previous study demonstrated a short survival period of infused MSCs and a lack of distribution of viable MSCs beyond the lungs[30]. The rapid clearance of infused UC-MSCs from the lungs is largely mediated by phagocytosis by monocytes, which induces phenotypic and functional changes in monocytes and triggers an immunomodulatory response[31]. UC-MSC administration in lipopolysaccharide (LPS)-induced ALI mice inhibits the expression of proinflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, IL-2, and interferon (IFN)-γ], enhances the expression of the anti-inflammatory cytokine IL-10, and reduces macrophage infiltration into injured lung tissue through prostaglandin E2 (PGE2)-dependent reprogramming of host macrophages to promote their expression of programmed cell death protein ligand 1[8]. IL-10 overexpression in UC-MSCs has been demonstrated to attenuate Escherichia coli (E. coli)-induced lung injury and increase macrophage function via the enhancement of macrophage phagocytosis and elimination of E. coli[32]. An in vitro model of PB mononuclear cell (PBMC) coculture with UC-MSCs demonstrated an immunomodulatory effect on PBMCs, namely, an increase in neutrophil activation, phagocytosis and leukocyte migration; activation of early T-cell markers; and a decrease in effector T cells and the senescent effector CD4. UC-MSCs exert their potent immunomodulatory effects through a PGE2-mediated mechanism, and a large amount of PGE2 produced by inflammatory cytokine-activated UC-MSCs is the principal mediator of immunosuppressive activities[33]. UC-MSC infusions significantly reduce the secretion of inflammatory biomarkers such as C-reactive protein (CRP), IL-6, IL-8, and TNF-α in COVID-19-induced ARDS patients[20]. MSCs interact with dendritic cells, regulating the balance between proinflammatory T-helper 1 (Th1) cells and anti-inflammatory Th2 cells via a shift toward the Th2 phenotype[34,35]. UC-MSC therapy has an inhibitory effect on overactive T-lymphocyte populations (CD8-CXCR3 and CD56-CXCR3) associated with cytokine storms, but the increase in CD4-CXCR3 in the UC-MSC group indicates the proliferation of these Th1 populations[36]. Recent studies have shown that UC-MSC transplantation leads to a decrease in inflammatory markers, such as the erythrocyte sedimentation rate and CRP level; more rapid recovery of blood lymphocytes; and reduced surfactant D, one of the main markers of lung injury. On the other hand, the production of proinflammatory cytokines, such as induced protein 10 kDa, macrophage inflammatory protein-1α, and granulocyte colony-stimulating factor, could suggest a greater immunomodulatory effect of MSCs than immunosuppression in COVID-19 patients[37]. Additionally, UC-MSC-derived extracellular vesicles (EVs) could mitigate the inflammatory response, restore the viability of cells and reduce the production of proinflammatory cytokines such as IL-8 and IL-1β in both LPS- and E. coli-induced lung injury models[38]. MSC-derived EVs can interact with immune cells and enhance macrophage phagocytosis through EV-mediated mitochondrial transfer[39].

MSCs, including UC-MSCs, possess regenerative and differentiation properties that contribute to tissue repair and regeneration. MSCs have been shown to stimulate local tissue regeneration by secreting paracrine factors associated with angiogenesis, antifibrosis effects and remodeling responses[40]. UC-MSCs secrete many molecules with paracrine effects that promote pulmonary alveolar regeneration and endothelial cell migration and proliferation, including angiopoietin-1, hepatocyte growth factor (HGF), epidermal growth factor, keratinocyte growth factor (KGF), vascular endothelial growth factor, MCP-1, C-X-C motif chemokine ligand (CXCL) 5 and matrix metalloprotease (MMP)[41]. UC-MSCs are more effective at restoring alveolar fluid clearance and protein permeability in influenza A (H5N1)-associated ALI and possess functional and practical advantages over conventional BM-MSCs[42]. In terms of their differentiation functions, UC-MSCs can be induced to differentiate into type II alveolar epithelial cells (AEC II), which are regarded as the progenitor cells of pulmonary epithelium and the target cells of pulmonary fibrosis[43]. In in vitro experiments, UC-MSC-derived AEC II were reported to be able to alleviate pulmonary fibrosis through regulating apoptosis mediated by β-catenin[44]. A recent study demonstrated that UC-MSCs ameliorate lung injury in ARDS and regulate Yes-associated protein to facilitate AEC II differentiation[45]. Furthermore, microvesicles derived from UC-MSCs were able to enhance alveolar development by promoting AEC II proliferation and ameliorating lung inflammation in an antenatal rat model of BPD[46]. In addition, UC-MSCs have antifibrotic properties and can secrete a variety of cytokines that effectively reverse pulmonary fibrosis[47]. UC-MSCs can alleviate bleomycin-induced pulmonary fibrosis in mice, and the overexpression of HGF has been proven to augment the antifibrotic effect of UC-MSCs by interacting with IL-17-producing cells in fibrotic lungs[48]. By demonstrating the reduction in inflammation and fibrosis induced by bleomycin-induced lung injury induced by UC-MSCs, a study showed that UC-MSCs increased MMP-2 levels and downregulated lung cytokine and tissue inhibitor of matrix metalloproteinase expression[49]. In coculture system studies, UC-MSCs elevated MMP-9 levels in pulmonary macrophages, released hyaluronan into the medium and promoted the expression of toll-like receptor-4 (TLR-4) in the lung for alveolar regeneration[50]. In the context of the molecular and cellular behavior of UC-MSCs, a subcluster of IFN-sensitive macrophages, which were identified by using cell sequencing after infusion, increased their expression of CXCL 9 and CXCL 10, which recruited more regulatory T cells into the injured lung; this indicated that UC-MSCs can attenuate pulmonary fibrosis via macrophages[51]. Moreover, a human UC mesenchymal cell-conditioned medium was shown to decrease the level of oxidative stress, proinflammatory cytokines, and malondialdehyde, which caused restorative and prophylactic effects against pulmonary fibrosis in a model of IPF[52].

In addition to their immunomodulatory and differentiation abilities, UC-MSCs also exhibit antimicrobial effects in patients with bacterial or viral pneumonia and the ensuing ALI. In an in vitro study, paracrine mediators such as KGF, antimicrobial polypeptides, defensins, and lipocalin 2 secreted by MSCs were found to enhance bacterial clearance[53,54]. Alternatively, the soluble paracrine factors released by MSCs, such as IL-10, PGE2, TNF-α-stimulated gene 6 and IL-6, also had preventive effects against microorganisms[54,55]. Antimicrobial peptides, such as the human cathelicidin hCAP-18/LL-37, exhibit direct antimicrobial activity against a series of related pathogens, including fungi, viruses, and both gram-positive and gram-negative bacteria[56]. Furthermore, β-defensin-2 (BD-2), which is secreted by UC-MSCs through the TLR-4 signaling pathway, is a critical paracrine factor that mediates the antibacterial and anti-inflammatory effects of these cells against E. coli-induced ALI in mice[57]. An in vitro study demonstrated that UC-MSCs possessed direct antimicrobial effects against bacteria and could alleviate antibiotic resistance, which was mediated partly by secretion of cathelicidin LL-37 and BD-2 and upregulation of outer membrane protein expression during bacterial infection[58]. In terms of the therapeutic effects of UC-MSCs on E. coli pneumonia, UC-MSCs were effective at reducing ALI, decreasing the bacterial load, improving oxygenation, reducing histological injury, and ameliorating the level of inflammatory markers[59]. On the other hand, the enhancement of macrophage phagocytosis and macrophage killing of E. coli was proposed as another main mechanism of the antimicrobial effects of IFN-γ-primed UC-MSCs[60].

OVERVIEW OF CLINICAL TRIAL REGISTRATIONS OF UC-MSCS FOR PULMONARY DISEASES

As of November 2023, when we searched for the keywords “human umbilical cord-derived mesenchymal stem cells” or “umbilical cord mesenchymal stem cells” or “UC-MSCs” and “pulmonary disease” or “coronavirus disease 2019” or “COVID-19” or “acute respiratory distress syndrome” or “ARDS” or “bronchopulmonary dysplasia” or “BPD” or “chronic obstructive pulmonary disease” or “COPD” or “pulmonary fibrosis” or “PF” in the Public Clinical Trial Database (https://ClinicalTrials.gov/), 55 clinical trials of pulmonary diseases worldwide were systematically reviewed; these diseases included COVID-19 (n = 17), ARDS (n = 14), BPD (n = 18), COPD (n = 3), and PF (n = 3). The geographical location and distribution of these clinical trials are shown in Figure 2. The clinical trials were conducted in 13 countries. Twenty-four clinical trials were conducted in China, followed by the United States, which hosted 9 trials. Korea was in third place with 7 trials. Clinical trials of pulmonary diseases have been increasingly conducted in developed and developing countries.

Figure 2
Figure 2 The geographical location and distribution of the clinical trials in pulmonary diseases.

The characteristics of the clinical trials, including study design, status and phase, were analyzed and counted (Figure 3). Thirty-two clinical trials were open-label; 1 was single-blinded for the participants; 3 were double-blinded for the participants and care providers; 11 were triple-blinded for the participants, care providers, and investigators; 7 were quadruple-blinded for the participants, care providers, investigators, and outcome assessors; and 1 was not described. Twenty-nine clinical trials were randomized, 7 were nonrandomized, and 19 did not provide relevant information. The intervention models included single-group assignment (n = 17), parallel assignment (n = 33), and sequential assignment (n = 2), while 3 were not described. The recruitment statuses of the clinical trials were as follows: Recruiting (n = 16), completed (n = 11), active but not recruiting (n = 5), not yet recruiting (n = 4), withdrawn (n = 4), or unknown (n = 15). The majority of clinical trials were mainly in the early phases, such as phase I studies evaluating safety (n = 24), phase II studies evaluating efficacy (n = 11), or combined phase I/II studies (n = 12). Additionally, only a very small number of clinical trials were phase III studies to determine pragmatic effectiveness (n = 2); 1 study was a combined phase II/III trial, and there were no phase IV trials to monitor long-term effects. Five trials did not specify the phase. The specific content and results are described as follows.

Figure 3
Figure 3 Characteristics of clinical trials involving umbilical cord-derived mesenchymal stem cells therapy for pulmonary diseases. A: Masking of clinical trials; B: Allocation of clinical trials; C: Intervention model of clinical trials; D: Status of clinical trials; E: Phase of clinical trials. N/A: Not available.
CURRENT RESEARCH ADVANCEMENTS IN THE USE OF UC-MSCS FOR PULMONARY DISEASES
UC-MSCs for COVID-19

COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has developed into a global pandemic and become the greatest public health threat in the 21st century[61]. People infected with SARS-CoV-2 have a wide range of clinical manifestations, ranging from asymptomatic or mild to severe respiratory symptoms, such as ARDS or multiple system organ failure, and death[62]. The host’s innate and adaptive immune responses associated with SARS-CoV-2 infection play a critical role in controlling virus replication[63]. Cytokine storms and excessive inflammation are considered the major causes of ARDS and multiple-organ damage, and they play important roles in the process of disease aggravation, especially in patients with severe COVID-19[64]. As of November 11, 2022, more than 630 million people were infected with COVID-19, and the number of deaths exceeded 6.6 million[65]. The serious sequelae of COVID-19 have a significant impact on health and quality of life[48]. At present, different potential treatment options for COVID-19, such as Paxlovid, recombinant soluble angiotensin-converting enzyme 2, monoclonal antibodies, antiviral molecules, IFN therapy, corticosteroids, herbal medicines, and vaccines, have been explored[66]. Considering the high impact that critical cases of COVID-19 still have on health and their complex pharmacological management, the search for new therapeutic approaches is urgent[67]. Research shows that MSCs have strong immunomodulatory and anti-inflammatory properties and can resist ARDS and cytokine storms in patients with COVID-19[68,69]. Since the outbreak of the pandemic, a series of clinical trials of MSC therapy have been conducted in an effort to resolve immune dysfunction caused by severe inflammation due to COVID-19.

To date, 17 clinical trials of UC-MSC treatments for COVID-19 have been registered in the Clinical Trial Database (Table 1). Consequently, 9 clinical trials were open-label; 1 clinical trial was single-blinded for the participants; 5 were triple-blinded for the participants, care providers, and investigators; and 2 were quadruple-blinded for the participants, care providers, investigators, and outcome assessors. Among all the eligible clinical trials, 14 were randomized, 1 was nonrandomized, and 2 did not provide relevant descriptions. The vast majority of clinical trials (n = 12) were in phase I, phase II or combined phase I/II, accounting for 70.5% of the total. Remarkably, only a small portion of the patients were in phase III (n = 2 or 11.8%). Therefore, most trials were in the early phases, and the results from these trials need to be further tested in advanced-phase trials. Among the 17 enrolled trials, 2 were completed; 1 was active but not recruiting; 3 were still recruiting; 2 were not yet recruiting; 2 were withdrawn; and 7 had an unknown status. The clinical trials were conducted in 6 countries. China hosted the largest number of clinical trials (n = 9), followed by the United States (n = 3) and Indonesia (n = 2). All 17 clinical trials were designed specifically for adults or older adults. UC-MSCs were usually administered intravenously once or multiple times, and the doses ranged from 0.5 × 106/kg to 1 × 106/kg per injection.

Table 1 Clinical trials of umbilical cord mesenchymal stem cells therapy for patients with coronavirus disease 2019.
NoTrial IDUC-MSCs administration protocol
PhaseStatusPatientsAge (yr)Follow-up timeMaskAllocationCountry
Frequency
Dose (cells)
Route
1NCT042936924 (at days 1, 3, 5 and 7)0.5 × 106/kgIVN/AWithdrawn4818-75N/ATriple-blindRandomizedChina
2NCT056825862 (at days 1 and 4)1 × 106/kgIVIIIRecruiting6018-75N/AOpen-labelRandomizedChina
3NCT055014181N/AIVI/IIActive, not recruiting7520-8012 monthsSingle-blindRandomizedChina
4NCT057190123 (at months 1, 2, and 3)N/AIVIINot yet recruiting7018-8096 wkTriple-blindRandomizedChina
5NCT042736464 (at days 1, 3, 5 and 7)0.5 × 106/kgIVN/AUnknown4818-6596 wkOpen-labelRandomizedChina
6NCT056890082 (at days 1 and 4)1 × 106/kgIVIIIRecruiting6018-85N/AOpen-labelRandomizedChina
7NCT0445760911 × 106/kgIVIUnknown4018-95N/ATriple-blindRandomizedIndonesia
8NCT051329723 (at days 0, 3, and 6)1 × 106/kgIVII/IIIRecruiting4218-7590 dQuadruple-blindRandomizedIndonesia
9NCT042881023 (at days 0, 3, and 6)4.0 × 107IVIICompleted10018-7590 dQuadruple-blindRandomizedChina
10NCT043662711N/AN/AIIWithdrawn10040-80N/AOpen-labelRandomizedSpain
11NCT043716014 (once every 4 d)1 × 106/kgIVIUnknown6018-70N/AOpen-labelRandomizedChina
12NCT0442976311 × 106/kgN/AIIUnknown3018-79N/ATriple-blindRandomizedUnited States
13NCT044619253 (at days 1,4 and 7)1 × 106/kgIVI/IIUnknown3018-75N/AOpen-labelNon-RandomizedUkraine
14NCT042695254 (at days 1, 3, 5 and 7)3.3 × 107IVIIUnknown1618-80N/AOpen-labelN/AChina
15NCT044378233 (at days 1, 3, and 5)0.5 × 106/kgIVIIUnknown2030-70N/AOpen-labelRandomizedPakistan
16NCT045732701N/AIVICompleted4018 to olderN/ATriple-blindRandomizedUnited States
17NCT052862552 (at days 1 and 4)1.25-1.5 × 106/kgIVINot yet recruiting1018-80N/AOpen-labelN/AUnited States

Many registered clinical trials have reported these findings. Shi et al[62] conducted a randomized, double-blind, and placebo-controlled phase II trial in which 65 severe COVID-19 patients with lung damage received UC-MSC treatment on days 0, 3, and 6 and 35 patients (control group) received placebo (NCT04288102). That study showed that, compared with the placebo, UC-MSC administration significantly improved the whole-lung lesion volume from baseline to day 28. The distance traveled in the 6-min walk test (6-MWT) was increased in patients treated with UC-MSCs. These results suggested that UC-MSC administration is a potentially safe and effective therapeutic treatment for COVID-19 patients with lung damage. To evaluate the effects of these interventions on reducing the mortality rate and preventing long-term pulmonary disability, a phase III trial is necessary in the future. In Jakarta, Indonesia, a double-blind, multicenter, randomized controlled trial at four COVID-19 referral hospitals was conducted by Dilogo et al[36] (NCT04457609). Forty randomly allocated critically ill patients with COVID-19 were included in this study; 20 patients were given a single intravenous infusion of 1 × 106 cells/kg body weight (BW) UC-MSCs in 100 mL of saline solution, and 20 patients received a placebo (100 mL of saline solution) as a control group. UC-MSC treatment significantly improved the survival rate of critically ill patients with COVID-19 by modulating the immune system toward an anti-inflammatory state. The survival rate in the UC-MSC group was 2.5 times greater than that in the control group, and the survival rate of patients with comorbidities was 4.5 times greater than that of the controls. Moreover, the intravenous administration of UC-MSCs was safe and well tolerated and did not cause life-threatening complications or acute allergic reactions. A randomized, double-blind phase II study involving 17 patients with COVID-19 also yielded encouraging results[70]. Compared to those in the placebo group, the levels of ferritin, IL-6, MCP1-CCL2, CRP, D-dimer, and neutrophil levels were lower, and the numbers of CD3+ and CD4+ T lymphocytes and NK cells were greater in the treatment group. These findings indicate that UC-MSC infusion plays an important role in the early prevention of severe complications and the reduction of sequelae in critically ill patients with COVID-19. Our research team also performed considerable work during the COVID-19 epidemic[71-74]. One of our previous studies reported the case of a 54-year-old patient with severe COVID-19 who receivedWharton’s jelly (WJ)-MSCs[75]. The pulmonary function and symptoms of the patient significantly improved 2 d after WJ-MSCs transplantation, and the patient recovered and was discharged 7 d after treatment. During the treatment period, the inflammatory indices and immune status of the COVID-19 patients significantly improved, which suggested that WJ-MSC transplantation may improve the prognosis of patients with COVID-19 by regulating the inflammatory response and promoting the recovery of antiviral immune cells and organs.

UC-MSCs for ARDS

ARDS, an acute respiratory condition in critically ill patients, is characterized by acute and refractory hypoxemia, noncardiogenic pulmonary edema, diffuse alveolar-capillary membrane damage, and reduced compliance (or increased lung stiffness)[5]. Patients with severe pneumonia induced by SARS-CoV-2 rapidly develop ARDS and die of multiple-organ failure[76]. The outbreak of COVID-19 has led to a significant increase in the number of ARDS patients worldwide. Despite advances in supportive therapies, ARDS still has very high mortality and long-term morbidity. In the United States, the incidence of ARDS ranges from 64.2 to 78.9 cases/100000 person-years[77]. Despite decades of basic and clinical research, there is still no safe and effective pharmacotherapy for ARDS. Therefore, there is an urgent need for new therapeutic methods to minimize lung tissue damage caused by inflammation and reduce the mortality rate in patients with ARDS. An increasing number of early clinical trials have verified the therapeutic potential of UC-MSC therapy, and the results of phase I/II clinical studies have demonstrated its feasibility, preliminary safety and efficacy in patients suffering from ARDS[78-80].

To date, 14 clinical trials assessing the safety and efficacy of UC-MSC therapy in ARDS patients have been registered (Table 2). These clinical trials were mainly conducted in the United States (n = 5) and China (n = 3) and accounted for 57% of the total. The main intervention models were single-group, parallel and sequential assignment. Among all the included clinical trials, 3 clinical trials involved single-group assignment, 8 involved parallel assignment, 2 involved sequential assignment, and 1 did not provide relevant information. Eight clinical trials were randomized, 2 were nonrandomized, and 4 did not report the allocation. Most trials (n = 12) were in the early phases, with the exception of 2 trials that were not described. All the clinical trials included adults and elderly individuals. Six clinical trials were open-label. In terms of the blinding design, 1 was double-blinded for the participants and care providers; 4 were triple-blinded for the participants, care providers, and investigators; and 2 were quadruple-blinded for the participants, care providers, investigators, and outcome assessors.

Table 2 Clinical trials of umbilical cord mesenchymal stem cells therapy for patients with acute respiratory distress syndrome.
NoTrial IDUC-MSCs administration protocol
PhaseStatusPatientsAge (yr)Follow-up timeMaskAllocationCountry
Frequency
Dose (cells)
Route
1NCT053872783 (at days 1, 3, 5 and 7)N/AIVIRecruiting2018-7512 wkQuadruple-blindRandomizedUnited States
2NCT0360859211 × 106/kgIVN/AUnknown2618 to olderN/AOpen-labelN/AChina
3NCT057410991N/AIVI/IIRecruiting2018-85N/ATriple-blindRandomizedChina
4NCT043557282 (within 24 h and within 72 h)1 × 108IVI/IICompleted2418 to olderN/ATriple-blindRandomizedUnited States
5NCT044520971Group 1: 0.5 × 106/kg; group 2: 1 × 106/kg; group 3:1.5 × 106/kgIVI/IINot yet recruiting3918-80N/AOpen-labelNon-randomizedChina
6NCT044943861/2 (at days 1 or 1 and 3)1 × 108IVI/IIActive, not recruiting6018 to older12 monthsTriple-blindRandomizedUnited States
7NCT0445636111 × 108IVIActive, not recruiting918 to older3 monthsOpen-labelN/AMexico
8NCT045656652 (at days 1 and within 7 d)N/AIVI/IIRecruiting7018 to older12 monthsOpen-labelRandomizedUnited States
9NCT030421431N/AIVIRecruiting12916 to olderN/AQuadruple-blindRandomizedUnited Kingdom
10NCT043479671N/AIVINot yet recruiting1820-85N/AOpen-labelN/AChina
11NCT043333683 (at days 1, 3 and 5)1 × 106/kgIV/CVCI/IICompleted4018 to older12 monthsTriple-blindRandomizedFrance
12NCT0524043011 × 106/kgIVN/ARecruiting118 to older4 wkN/AN/ATurkey
13NCT044000323 (at days 1, 2, and 3)Group 1: 7.5 × 107, group 2: 1.5 × 108, group 3: 2.7 × 108IVI/IICompleted1518 to olderN/AOpen-labelNon-randomizedCanada
14NCT044904862 (at days 0 and 3)1 × 108IVIWithdrawn2118 to olderN/ADouble-blindRandomizedUnited States

To evaluate the safety and explore the possibility of three injections of UC-MSCs in patients with mild-moderate ARDS induced by COVID-19, a single-center, open-label, phase I clinical trial with a placebo-control group was conducted at Imam Reza Hospital[81]. Ten patients in the intervention group received three intravenous infusions of UC-MSCs (1 × 106 cells/kg BW per injection) on days 1, 3 and 5, and 10 patients in the placebo-control group were administered normal saline. The follow-up period in this clinical trial was 17 d. According to their results, the SPO2/FIO2 ratio and serum CRP levels were significantly improved, and the serum inflammatory cytokines (IL-6, IFN-γ, TNF-α and IL-17A) were also significantly reduced after UC-MSC intravenous infusion, which demonstrated that multiple transplantations of UC-MSCs can decrease cytokine storms and ameliorate respiratory functions. Monsel et al[82] conducted a double-blind, multicenter trial for the treatment of SARS-CoV-2-induced ARDS (NCT04333368). Among these patients, 21 patients were randomly assigned to receive 3 rounds of intravenous infusions of UC-MSCs (1 × 106/kg per infusion) over 5 d after recruitment, and 24 patients received saline (0.9%) solution as the control. There was no significant difference in the incidence of infusion-associated adverse events (AEs) between these two groups, and no serious AEs linked to UC-MSC infusion were observed. These findings suggest that intravenous administration of UC-MSCs is safe for patients with SARS-CoV-2-induced ARDS. A phase I/II randomized, double-blind, placebo-controlled trial of 24 patients was conducted in the UHealth System/Jackson Health System in Miami, Florida (NCT04355728)[21]. In this study, 12 ARDS patients received two intravenous infusions (at days 0 and 3) of UC-MSCs; controls received two infusions of vehicle solution. The results showed that the 31-d mortality rate was 9% in the UC-MSC treatment arm and 58% in the control arm. After UC-MSC treatment, lung inflammation in ARDS patients was alleviated, and this change was accompanied by a significant decrease in inflammatory factor levels. In addition, the UC-MSC-treated group exhibited a shorter recovery time than the control group. Severe UC-MSC infusion-related AEs were not observed in either group. Therefore, UC-MSC infusion may be a safe and effective treatment option for ARDS patients. To explore the maximum tolerable dose of infused UC-MSCs, Yip et al[83] administered different doses of UC-MSCs (1.0 × 106 cells/kg, 5.0 × 106 cells/kg, 1.0 × 107 cells/kg) intravenously to 9 patients with moderate to severe ARDS. Their results demonstrated that a single intravenous UC-MSC infusion of up to 1.0 × 107 cells/kg was excellently tolerated in ARDS patients without serious AEs. Interestingly, several inflammatory indicators (i.e., CD11b+/CD16+, CD11b+/MPO+, CD16+/MPO+, and CD14+CD33+) substantially decreased on the first day after cell infusion, followed by a significant gradual increase from day 3 to day 7, and then a significant decrease compared to baseline treatment on the 30th d after cell infusion. Therefore, the anti-inflammatory effect of single-dose UC-MSC reinfusion in the human body may have a certain timeliness.

UC-MSCs for BPD

BPD is a chronic lung disease in premature infants that is characterized by the arrest of alveolarization, fibroblast activation, and inflammation. Many risk factors can increase a baby’s risk of developing BPD, including premature birth, oxygen poisoning, intrauterine growth delay, smoking, ventilation support, infection, inflammation, patent ductus arteriosus, congenital factors, and immature lung development[84-88]. The pathogenesis of BPD involves a variety of pathophysiological factors, including abnormal angiogenesis, inflammation, oxidative stress, and impaired lung repair[89]. Epidemiological studies have shown that the incidence of BPD in very preterm infants increases with decreasing gestational age and birth weight and reaches as high as 40%[90,91]. BPD can affect the nervous, circulatory and respiratory systems and has a serious impact on the survival rate and quality of life of premature infants[92]. Despite major advances in understanding disease pathologies, there is no single treatment or combination therapy available for preventing or treating BPD. As a more promising novel therapeutic option, MSCs have been widely used in clinical practice due to their anti-inflammatory and paracrine effects. MSCs can also contribute to the repair of lung injuries by restoring the integrity of lung epithelial/endothelial cells, which provides a new approach for the application of MSCs in BPD[93,94].

There were 18 registered clinical trials using UC-MSCs for the treatment of BPD (Table 3). These clinical trials were mainly conducted in five countries, namely, China, South Korea, Vietnam, Canada and the United States. In terms of grouping design, 6 clinical trials used single-group assignment, 10 used parallel assignment, and 2 did not describe the grouping design. Only 10 trials, including randomized (n = 7) and nonrandomized (n = 3) studies, provided necessary descriptions of random allocation. There were 10 phase I clinical trials, 4 phase II trials, and 3 phase I/II trials, accounting for 56%, 22%, and 17%, respectively. Twelve clinical trials were open-label; 1 was double-blinded for the participants and care providers; 3 were triple-blinded for the participants, care providers, and investigators; and 3 were quadruple-blinded for the participants, care providers, investigators, and outcome assessors.

Table 3 Clinical trials of umbilical cord mesenchymal stem cells therapy for patients with bronchopulmonary dysplasia.
NoTrial IDUC-MSCs administration protocol
PhaseStatusPatientsAgeFollow-up timeMaskAllocationCountry
Frequency
Dose (cells)
Route
1NCT040621362 (at days 1 and 8)1 × 106/kgIVIUnknown101-6 monthsN/AOpen-labelN/AVietnam
2NCT023813661Dose A: 1 × 107/kg; dose B: 2 × 107/kgN/AI/IICompleted123-14 dN/AOpen-labelN/AUnited States
3NCT0364552512 × 107/kgEndobronchialI/IIRecruiting1802-3 wkN/AQuadruple-blindRandomizedChina
4NCT036014161Dose A: 1 × 106/kg, dose B: 5 × 106/kgIVIIUnknown2128 d to 1 yrN/AOpen-labelRandomizedChina
5NCT035583341Dose A: 1 × 106/kg, dose B: 5 × 106/kgIVIUnknown1228 d and olderN/AOpen-labelNon-randomizedChina
6NCT0120786913 × 106/kgEndobronchialIUnknown101 wk to 6 monthsN/ADouble-blindRandomizedChina
7NCT038735061Dose A: 1 × 106/kg, dose B: 5 × 106/kgIVIUnknown301 months to 5 yrN/AOpen-labelN/AChina
8NCT037745371Dose A: 1 × 106/kg, dose B: 5 × 106/kgIVI/IIUnknown204-14 dN/AOpen-labelNon-randomizedChina
9NCT036314201Dose A: 3 × 106/kg, dose B: 1 × 107/kg, dose C: 3 × 107/kgN/AIRecruiting93-51 dN/AOpen-labelN/AChina
10NCT016324751Dose A: 1 × 107/kg, dose B: 2 × 107/kgIVIActive, not recruiting94 months to 2 yrN/AOpen-labelN/AKorea
11NCT012972051Dose A: 1 × 107/kg, dose B: 2 × 107/kgIVICompleted95-14 dN/AOpen-labelN/AKorea
12NCT0400385711 × 107/kgIVIIRecruiting606-60 monthsN/ATriple-blindRandomizedKorea
13NCT0189798711 × 107/kgIVN/ACompleted627 months60 monthsTriple-blindRandomizedKorea
14NCT0182895711 × 107/kgIVIICompleted695-14 dN/AQuadruple-blindRandomizedKorea
15NCT020237881Dose A: 1 × 107/kg, dose B: 2 × 107/kgIVICompleted845-63 months5 yrOpen-labelN/AKorea
16NCT033780631N/AN/AIWithdrawn1001-3 monthsN/AOpen-labelNon-randomizedChina
17NCT033924671N/AN/AIIRecruiting60Up to 13 dN/AQuadruple-blindRandomizedKorea
18NCT042551471Dose A: 1 × 106/kg, dose B: 3 × 106/kg, dose C: 1 × 107/kgIVIRecruiting97-28 dN/AOpen-labelN/ACanada

Moreira et al[95] studied the feasibility and effectiveness of nasal administration of UC-MSCs in the treatment of hyperoxia-induced BPD in a rat model. Lung alveolarization, vascularization, and pulmonary vascular remodeling were restored in BPD rats receiving UC-MSC treatment. The results of the gene and protein analyses indicated that the beneficial effects of UC-MSCs were partially attributed to collaborative efforts targeting angiogenesis, immune regulation, cell survival, and wound healing. Gene and protein analyses suggest that the beneficial effects of UC-MSCs are due in part to concerted efforts targeting immune regulation, angiogenesis, cell survival, and wound healing. Therefore, nasal administration of UC-MSCs for BPD treatment is a noninvasive, feasible route of administration with potential for widespread clinical application. Many registered clinical trials have also published their research findings. A study conducted by Chang et al[96] included 9 patients with preterm infants at high risk for BPD (NCT01297205). The first three patients received a low dose of UC-MSCs intratracheally administered at a concentration of 1 × 107 cells/kg BW, while the subsequent six patients received a high dose of UC-MSCs intratracheally administered at a concentration of 2 × 107 cells/kg BW. No AEs related to infusion were observed. The levels of IL-6, IL-8, MMP-9, TNF-α, and transforming growth factor-β1 in tracheal aspirate fluid were significantly decreased after UC-MSC transplantation. Among the 9 infants who received UC-MSC transplantation, only 3 developed moderate BPD, which showed that UC-MSCs could significantly lower BPD severity. The intratracheal transplantation of UC-MSCs was found to be safe and feasible for preterm infants. In a phase I dose-escalation trial involving 2 dosing regimens, Powell and Silvestri[97] investigated the safety and efficacy of intratracheal administration of UC-MSCs (NCT02381366). In this trial, 12 preterm infants at the highest risk for BPD were randomized into two groups. In this study, 12 premature infants with BPD received two doses of UC-MSCs (low dose, 1 × 106 cells/kg; high dose, 2 × 107 cells/kg) via endotracheal administration. All patients completed the 84-d follow-up. The 12 patients tolerated the treatment well, with no reports of dose-limiting toxicity within the first 72 h. Additionally, no serious AEs related to the drug were observed during the 84 d in this study. Based on the above studies, UC-MSCs may be a safe and effective treatment method for BPD.

UC-MSCs for COPD

COPD is a chronic inflammatory lung disease caused by airway and alveolar abnormalities, and irreversible airway limitation is a common feature[98]. According to the World Health Organization, COPD will become the third leading cause of death by 2030 and represents a considerable burden on the health-care system[99]. At present, the pathogenesis of COPD is mainly the result of interactions between genetic factors and acquired factors, but the exact pathological mechanism is still unclear[100]. Some studies have suggested that smoking is the main environmental factor triggering COPD, but other factors also include airway hyperresponsiveness, sex, genetics, occupation, lung growth, and development[101,102]. Currently available treatment methods for COPD, which mainly focus on treating the symptoms and slowing the progression of these disorders, include anti-inflammatory drugs, corticosteroids, long-acting muscarinic antagonists, and β2-adrenergic receptor agonists[103,104]. These treatments may help minimize airflow limitation and future exacerbations but cannot reverse lung damage or improve quality of life in patients with COPD. Recent advances in cell therapy have demonstrated that MSCs are safe and effective at improving quality of life and clinical conditions and are potential candidates for clinical use in the treatment of COPD[105].

Currently, the use of a total of 3 UC-MSC transplantations is being verified in clinical trials for the treatment of COPD (Table 4). These clinical trials are being conducted in China, Vietnam, Antigua, and Barbuda, all of which are in early phases. Río et al[106] conducted a preclinical study using UC-MSC cellular therapy for COPD. They tested the therapeutic effects of different routes of administration (intravenously and intratracheally) on COPD mice and analyzed the relevant molecular changes through protein array analysis. The results showed that UC-MSCs can effectively reduce lung emphysema regardless of the administration route and modify the inflammatory profile in elastase-treated mice, which is most likely due to mitochondrial transfer, immunomodulation, and homing to the injured areas. In the clinical study conducted by Le Thi Bich et al[19], 20 patients with COPD (9 at stage C and 11 at stage D according to the Global Initiative for Obstructive Lung Disease classification) were infused with 1 × 106 cells/kg of expanded allogeneic UC-MSCs. After 6 months of follow-up, the COPD incidence, Modified Medical Research Council score, and number of exacerbations were significantly lower in patients who underwent UC-MSC transplantation than in those who did not. No UC-MSC infusion-related toxicity or death occurred during the administration process. However, there were no significant decreases in the forced expiratory volume in 1 s, CRP, or 6-MWT values after treatment (at 1, 3, and 6 months, respectively) compared to the corresponding values before treatment. In summary, in vitro and in vivo research results suggest that UC-MSCs may be a safe and effective treatment method for moderate-to-severe COPD and are worthy of further clinical promotion.

Table 4 Clinical trials of umbilical cord mesenchymal stem cells therapy for patients with chronic obstructive pulmonary disease.
NoTrial IDUC-MSCs administration protocol
PhaseStatusPatientsAge (yr)Follow-up timeMaskAllocationCountry
Frequency
Dose (cells)
Route
1NCT044331042 (at mo 1 and 4)1 × 106/kgIVIIUnknown4040-7512 monthsSingle-blindNon-RandomizedVietnam
2NCT042060071N/AIVIActive, not recruiting940-7548 monthsOpen labelN/AChina
3NCT0514768811 × 108IVIRecruiting20Child, adult, older adult48 monthsOpen-labelN/AAntigua and Barbuda
UC-MSCs for PF

PF is a chronic progressive lung disease that eventually leads to death and respiratory failure and is characterized by inflammation and fibrosis of the interstitium and destruction of the alveolar histoarchitecture[48,107]. There are various risk factors that initiate lung tissue damage and PF, including smoking, virus or bacterial infections, autoimmune reactions, air irritants, chemotherapy, ionizing radiation, and pollutants[108-110]. IPF, regarded as the most common type of pulmonary fibrosis, is a progressive disease of the lower respiratory tract with an incidence of 4.6 to 16.3 cases per 100000 worldwide[111]. Despite decades of scientific research, the factors involved in the onset of the histopathological cascade in PF have not been identified. Currently, there are no effective therapeutic approaches for preventing pulmonary fibrosis development. Emerging MSC-based therapy has been shown to be a new and promising therapeutic strategy due to its anti-inflammatory and antifibrotic effects, and accumulating evidence indicates that MSC transplantation potentially alleviates and ameliorates PF[112-114]. Many studies have revealed the beneficial treatment effects of MSC administration in patients with PF[115,116].

According to the ClinicalTrials.gov website, a total of 3 clinical trials focused on UC-MSC-based therapy for PF were registered (Table 5). All 3 clinical trials were phase I. Two trials are currently being recruiting, and 1 has been completed. UC-MSCs are usually administered intravenously once, and the doses range from 1 × 106 cells/kg to 1 × 108 cells/kg per injection. Currently, there are no published results corresponding to registered clinical trials. da Silva et al[117] reported a case in which a 30-year-old patient with COVID-19 progressed to PF and received UC-MSCs (5 × 107, 2 doses 2 d apart). After UC-MSC treatment, improvements in the patient’s chest computed tomography scan were observed, with a decrease in ground-glass opacity and pneumonia infiltration, as well as an increase in the PaO2/FiO2 ratio and a reduction in the need for vasoactive drugs. Simultaneously, modulation of different cell populations in the PB was also observed, as indicated by a reduction in inflammatory monocytes and an increase in the frequency of patrolling monocytes, type 2 classical dendritic cells, and CD4+ lymphocytes. These findings suggested that UC-MSC therapy may be a potential treatment option for critically ill patients with fibrosis caused by COVID-19. Unfortunately, considering the limited number of published results, the effectiveness and safety of UC-MSCs for treating PF still require additional high-quality multicenter clinical trials for further confirmation.

Table 5 Clinical trials of umbilical cord mesenchymal stem cells therapy for patients with pulmonary fibrosis.
NoTrial IDUC-MSCs administration protocol
PhaseStatusPatientsAge (yr)Follow-up timeMaskAllocationCountry
Frequency
Dose (cells)
Route
1NCT054685021Dose A: 6.0 × 106, dose B: 3.0 × 107, dose C: 6.0 × 107, dose D: 9.0 × 107IVIRecruiting1850-75N/AOpen-labelN/AChina
2NCT0227714511 × 106/kgIVICompleted10Adult, older adultN/AOpen-labelN/AChina
3NCT0501681711 × 108IVIRecruiting20Child, adult, older adult48 monthsOpen-labelN/AAntigua and Barbuda, Argentina, Mexico
CONCLUSION

With the increasing use of UC-MSC therapy for clinical treatment, UC-MSC-based therapy approaches are continuing to evolve at a rapid pace, especially for treating currently incurable and devastating lung diseases. However, many problems remain to be solved, such as the number of cells, transplantation routes, and mechanism of action. To date, however, a comprehensive systematic analysis of clinical trials from the Public Clinical Trial Database has not been published. In this study, 55 clinical trials of pulmonary diseases worldwide were systematically analyzed. These clinical trials were widely distributed and conducted in 13 countries. Currently, these clinical trials have several limitations. For example, 63.6% of clinical trials are in the early phases, during which safety has largely been demonstrated. The relatively small number of recruited subjects has also been a prominent limitation in these clinical trials. There are certain disparities caused by the different groups of recruited participants, therapeutic regimens and doses and frequencies of UC-MSCs in previous clinical trials. In addition, among the 55 clinical trials included in this study, 11 trials were completed. To date, available data from published clinical studies have proven the safety and efficacy of UC-MSC therapy for various lung diseases, with few infusion-related reactions and late adverse effects. In particular, the great majority of clinical trials were recruiting or active but not recruiting. Therefore, the current positive conclusions about the prevention or treatment of lung diseases by UC-MSCs need to be further validated and evaluated.

Although great progress has been made in preclinical and clinical studies of UC-MSC therapy, there are still substantial challenges in the clinical setting. According to the summary analysis of registered clinical trials, factors such as donor selection, culture conditions, cell consistency, dosage of UC-MSCinfusion, long-term therapeutic effects, and potential tumorigenicity remain the bottlenecks in clinical treatment mediated by UC-MSCs. Standardization of the evaluation of UC-MSCs was lacking, which was an important problem for cell viability and homing. The use of UC-MSCs in clinical practice requires a large number of cells; however, long-term in vitro culture and continuous passages of UC-MSCs may exert important influences on phenotypic characterization and biological function. Thus, UC-MSCs require a standard treatment protocol, such as donor sources, cell usage and dosage, manufacturing protocols, quality control, and delivery routes. Before clinical application, a series of tests, including bacteriological tests, viability and phenotype tests, oncogenicity tests, and endotoxin assays, should be carefully performed to ensure cell quality control. These challenging questions regarding UC-MSC therapy need to be addressed, as they could contribute to the translation of cell therapy from bench to bedside for patients suffering from lung diseases. To determine the long-term efficacy of UC-MSC therapy for lung disease, prospective, multicenter, randomized, controlled and long-term follow-up clinical trials with large sample sizes are still necessary.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Cell and tissue engineering

Country/Territory of origin: China

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Li SC, United States S-Editor: Wang JJ L-Editor: Webster JR P-Editor: Yuan YY

References
1.  Sueblinvong V, Weiss DJ. Stem cells and cell therapy approaches in lung biology and diseases. Transl Res. 2010;156:188-205.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 92]  [Cited by in F6Publishing: 90]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
2.  Murray CJL. COVID-19 will continue but the end of the pandemic is near. Lancet. 2022;399:417-419.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 144]  [Cited by in F6Publishing: 112]  [Article Influence: 56.0]  [Reference Citation Analysis (0)]
3.  Hoang DM, Pham PT, Bach TQ, Ngo ATL, Nguyen QT, Phan TTK, Nguyen GH, Le PTT, Hoang VT, Forsyth NR, Heke M, Nguyen LT. Stem cell-based therapy for human diseases. Signal Transduct Target Ther. 2022;7:272.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 158]  [Article Influence: 79.0]  [Reference Citation Analysis (0)]
4.  GBD Chronic Respiratory Disease Collaborators. Prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med. 2020;8:585-596.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 661]  [Cited by in F6Publishing: 865]  [Article Influence: 216.3]  [Reference Citation Analysis (0)]
5.  ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307:2526-2533.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1812]  [Cited by in F6Publishing: 4025]  [Article Influence: 335.4]  [Reference Citation Analysis (0)]
6.  Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, Herridge M, Randolph AG, Calfee CS. Acute respiratory distress syndrome. Nat Rev Dis Primers. 2019;5:18.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 913]  [Cited by in F6Publishing: 1195]  [Article Influence: 239.0]  [Reference Citation Analysis (0)]
7.  Bos LDJ, Ware LB. Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes. Lancet. 2022;400:1145-1156.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 111]  [Article Influence: 55.5]  [Reference Citation Analysis (0)]
8.  Tu C, Wang Z, Xiang E, Zhang Q, Zhang Y, Wu P, Li C, Wu D. Human Umbilical Cord Mesenchymal Stem Cells Promote Macrophage PD-L1 Expression and Attenuate Acute Lung Injury in Mice. Curr Stem Cell Res Ther. 2022;17:564-575.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 3]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
9.  Fan E, Brodie D, Slutsky AS. Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment. JAMA. 2018;319:698-710.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 733]  [Cited by in F6Publishing: 837]  [Article Influence: 139.5]  [Reference Citation Analysis (0)]
10.  Chen X, Wang F, Huang Z, Wu Y, Geng J, Wang Y. Clinical applications of mesenchymal stromal cell-based therapies for pulmonary diseases: An Update and Concise Review. Int J Med Sci. 2021;18:2849-2870.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 4]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
11.  Abbaszadeh H, Ghorbani F, Abbaspour-Aghdam S, Kamrani A, Valizadeh H, Nadiri M, Sadeghi A, Shamsasenjan K, Jadidi-Niaragh F, Roshangar L, Ahmadi M. Chronic obstructive pulmonary disease and asthma: mesenchymal stem cells and their extracellular vesicles as potential therapeutic tools. Stem Cell Res Ther. 2022;13:262.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 19]  [Article Influence: 9.5]  [Reference Citation Analysis (0)]
12.  Liu X, Fang Q, Kim H. Preclinical Studies of Mesenchymal Stem Cell (MSC) Administration in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review and Meta-Analysis. PLoS One. 2016;11:e0157099.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 33]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
13.  Ridzuan N, Zakaria N, Widera D, Sheard J, Morimoto M, Kiyokawa H, Mohd Isa SA, Chatar Singh GK, Then KY, Ooi GC, Yahaya BH. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles ameliorate airway inflammation in a rat model of chronic obstructive pulmonary disease (COPD). Stem Cell Res Ther. 2021;12:54.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 39]  [Article Influence: 13.0]  [Reference Citation Analysis (0)]
14.  Stucky A, Gao L, Li SC, Tu L, Luo J, Huang X, Chen X, Li X, Park TH, Cai J, Kabeer MH, Plant AS, Sun L, Zhang X, Zhong JF. Molecular Characterization of Differentiated-Resistance MSC Subclones by Single-Cell Transcriptomes. Front Cell Dev Biol. 2022;10:699144.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
15.  Zhou T, Yuan Z, Weng J, Pei D, Du X, He C, Lai P. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol. 2021;14:24.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 62]  [Cited by in F6Publishing: 228]  [Article Influence: 76.0]  [Reference Citation Analysis (0)]
16.  El Omar R, Beroud J, Stoltz JF, Menu P, Velot E, Decot V. Umbilical cord mesenchymal stem cells: the new gold standard for mesenchymal stem cell-based therapies? Tissue Eng Part B Rev. 2014;20:523-544.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 174]  [Cited by in F6Publishing: 194]  [Article Influence: 19.4]  [Reference Citation Analysis (0)]
17.  Bartolucci J, Verdugo FJ, González PL, Larrea RE, Abarzua E, Goset C, Rojo P, Palma I, Lamich R, Pedreros PA, Valdivia G, Lopez VM, Nazzal C, Alcayaga-Miranda F, Cuenca J, Brobeck MJ, Patel AN, Figueroa FE, Khoury M. Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure: A Phase 1/2 Randomized Controlled Trial (RIMECARD Trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy]). Circ Res. 2017;121:1192-1204.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 216]  [Cited by in F6Publishing: 272]  [Article Influence: 38.9]  [Reference Citation Analysis (0)]
18.  Kamen DL, Wallace C, Li Z, Wyatt M, Paulos C, Wei C, Wang H, Wolf BJ, Nietert PJ, Gilkeson G. Safety, immunological effects and clinical response in a phase I trial of umbilical cord mesenchymal stromal cells in patients with treatment refractory SLE. Lupus Sci Med. 2022;9.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 5]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
19.  Le Thi Bich P, Nguyen Thi H, Dang Ngo Chau H, Phan Van T, Do Q, Dong Khac H, Le Van D, Nguyen Huy L, Mai Cong K, Ta Ba T, Do Minh T, Vu Bich N, Truong Chau N, Van Pham P. Allogeneic umbilical cord-derived mesenchymal stem cell transplantation for treating chronic obstructive pulmonary disease: a pilot clinical study. Stem Cell Res Ther. 2020;11:60.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 27]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
20.  Hashemian SR, Aliannejad R, Zarrabi M, Soleimani M, Vosough M, Hosseini SE, Hossieni H, Keshel SH, Naderpour Z, Hajizadeh-Saffar E, Shajareh E, Jamaati H, Soufi-Zomorrod M, Khavandgar N, Alemi H, Karimi A, Pak N, Rouzbahani NH, Nouri M, Sorouri M, Kashani L, Madani H, Aghdami N, Vasei M, Baharvand H. Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series. Stem Cell Res Ther. 2021;12:91.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 84]  [Cited by in F6Publishing: 117]  [Article Influence: 39.0]  [Reference Citation Analysis (0)]
21.  Lanzoni G, Linetsky E, Correa D, Messinger Cayetano S, Alvarez RA, Kouroupis D, Alvarez Gil A, Poggioli R, Ruiz P, Marttos AC, Hirani K, Bell CA, Kusack H, Rafkin L, Baidal D, Pastewski A, Gawri K, Leñero C, Mantero AMA, Metalonis SW, Wang X, Roque L, Masters B, Kenyon NS, Ginzburg E, Xu X, Tan J, Caplan AI, Glassberg MK, Alejandro R, Ricordi C. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021;10:660-673.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 266]  [Cited by in F6Publishing: 230]  [Article Influence: 76.7]  [Reference Citation Analysis (0)]
22.  Hass R, Kasper C, Böhm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011;9:12.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1018]  [Cited by in F6Publishing: 1115]  [Article Influence: 85.8]  [Reference Citation Analysis (0)]
23.  Zhou C, Wang W, Mu Y. Allogeneic Mesenchymal Stem Cells Therapy for the Treatment of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure. Hepatology. 2018;68:1660-1661.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
24.  Heo JS, Choi Y, Kim HS, Kim HO. Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue. Int J Mol Med. 2016;37:115-125.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 238]  [Cited by in F6Publishing: 289]  [Article Influence: 32.1]  [Reference Citation Analysis (0)]
25.  Watson N, Divers R, Kedar R, Mehindru A, Borlongan MC, Borlongan CV. Discarded Wharton jelly of the human umbilical cord: a viable source for mesenchymal stromal cells. Cytotherapy. 2015;17:18-24.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 88]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
26.  Shang Y, Guan H, Zhou F. Biological Characteristics of Umbilical Cord Mesenchymal Stem Cells and Its Therapeutic Potential for Hematological Disorders. Front Cell Dev Biol. 2021;9:570179.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 23]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
27.  Behnke J, Kremer S, Shahzad T, Chao CM, Böttcher-Friebertshäuser E, Morty RE, Bellusci S, Ehrhardt H. MSC Based Therapies-New Perspectives for the Injured Lung. J Clin Med. 2020;9.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 97]  [Article Influence: 24.3]  [Reference Citation Analysis (0)]
28.  Jin HJ, Bae YK, Kim M, Kwon SJ, Jeon HB, Choi SJ, Kim SW, Yang YS, Oh W, Chang JW. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci. 2013;14:17986-18001.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 409]  [Cited by in F6Publishing: 420]  [Article Influence: 38.2]  [Reference Citation Analysis (0)]
29.  Lanzoni G, Linetsky E, Correa D, Alvarez RA, Marttos A, Hirani K, Cayetano SM, Castro JG, Paidas MJ, Efantis Potter J, Xu X, Glassberg M, Tan J, Patel AN, Goldstein B, Kenyon NS, Baidal D, Alejandro R, Vianna R, Ruiz P, Caplan AI, Ricordi C. Umbilical Cord-derived Mesenchymal Stem Cells for COVID-19 Patients with Acute Respiratory Distress Syndrome (ARDS). CellR4 Repair Replace Regen Reprogram. 2020;8.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 4]  [Reference Citation Analysis (0)]
30.  Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, Baan CC, Dahlke MH, Hoogduijn MJ. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol. 2012;3:297.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 439]  [Cited by in F6Publishing: 512]  [Article Influence: 42.7]  [Reference Citation Analysis (0)]
31.  de Witte SFH, Luk F, Sierra Parraga JM, Gargesha M, Merino A, Korevaar SS, Shankar AS, O'Flynn L, Elliman SJ, Roy D, Betjes MGH, Newsome PN, Baan CC, Hoogduijn MJ. Immunomodulation By Therapeutic Mesenchymal Stromal Cells (MSC) Is Triggered Through Phagocytosis of MSC By Monocytic Cells. Stem Cells. 2018;36:602-615.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 266]  [Cited by in F6Publishing: 326]  [Article Influence: 54.3]  [Reference Citation Analysis (0)]
32.  Jerkic M, Masterson C, Ormesher L, Gagnon S, Goyal S, Rabani R, Otulakowski G, Zhang H, Kavanagh BP, Laffey JG. Overexpression of IL-10 Enhances the Efficacy of Human Umbilical-Cord-Derived Mesenchymal Stromal Cells in E. coli Pneumosepsis. J Clin Med. 2019;8.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 32]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
33.  Chen K, Wang D, Du WT, Han ZB, Ren H, Chi Y, Yang SG, Zhu D, Bayard F, Han ZC. Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism. Clin Immunol. 2010;135:448-458.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 141]  [Cited by in F6Publishing: 136]  [Article Influence: 9.7]  [Reference Citation Analysis (0)]
34.  Gustine JN, Jones D. Immunopathology of Hyperinflammation in COVID-19. Am J Pathol. 2021;191:4-17.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 323]  [Cited by in F6Publishing: 303]  [Article Influence: 101.0]  [Reference Citation Analysis (0)]
35.  Pontes Ferreira C, Moro Cariste L, Henrique Noronha I, Fernandes Durso D, Lannes-Vieira J, Ramalho Bortoluci K, Araki Ribeiro D, Golenbock D, Gazzinelli RT, Vasconcelos JRC. CXCR3 chemokine receptor contributes to specific CD8+ T cell activation by pDC during infection with intracellular pathogens. PLoS Negl Trop Dis. 2020;14:e0008414.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 6]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
36.  Dilogo IH, Aditianingsih D, Sugiarto A, Burhan E, Damayanti T, Sitompul PA, Mariana N, Antarianto RD, Liem IK, Kispa T, Mujadid F, Novialdi N, Luviah E, Kurniawati T, Lubis AMT, Rahmatika D. Umbilical cord mesenchymal stromal cells as critical COVID-19 adjuvant therapy: A randomized controlled trial. Stem Cells Transl Med. 2021;10:1279-1287.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 93]  [Article Influence: 31.0]  [Reference Citation Analysis (0)]
37.  Bukreieva T, Svitina H, Nikulina V, Vega A, Chybisov O, Shablii I, Ustymenko A, Nemtinov P, Lobyntseva G, Skrypkina I, Shablii V. Treatment of Acute Respiratory Distress Syndrome Caused by COVID-19 with Human Umbilical Cord Mesenchymal Stem Cells. Int J Mol Sci. 2023;24.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
38.  Gonzalez H, McCarthy S, Masterson C, Byrnes D, Sallent I, Horan E, Elliman SJ, Vella G, Prina-Mello A, Silva JD, Krasnodembskaya AD, MacLoughlin R, Laffey JG, O'Toole D. Nebulised mesenchymal stem cell derived extracellular vesicles ameliorate E. coli induced pneumonia in a rodent model. Stem Cell Res Ther. 2023;14:151.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 3]  [Reference Citation Analysis (0)]
39.  Morrison TJ, Jackson MV, Cunningham EK, Kissenpfennig A, McAuley DF, O'Kane CM, Krasnodembskaya AD. Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. Am J Respir Crit Care Med. 2017;196:1275-1286.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 361]  [Cited by in F6Publishing: 466]  [Article Influence: 66.6]  [Reference Citation Analysis (0)]
40.  Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int J Mol Sci. 2017;18.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 548]  [Cited by in F6Publishing: 713]  [Article Influence: 101.9]  [Reference Citation Analysis (0)]
41.  Burlacu A, Grigorescu G, Rosca AM, Preda MB, Simionescu M. Factors secreted by mesenchymal stem cells and endothelial progenitor cells have complementary effects on angiogenesis in vitro. Stem Cells Dev. 2013;22:643-653.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 120]  [Cited by in F6Publishing: 123]  [Article Influence: 10.3]  [Reference Citation Analysis (0)]
42.  Loy H, Kuok DIT, Hui KPY, Choi MHL, Yuen W, Nicholls JM, Peiris JSM, Chan MCW. Therapeutic Implications of Human Umbilical Cord Mesenchymal Stromal Cells in Attenuating Influenza A(H5N1) Virus-Associated Acute Lung Injury. J Infect Dis. 2019;219:186-196.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 94]  [Cited by in F6Publishing: 91]  [Article Influence: 18.2]  [Reference Citation Analysis (0)]
43.  Desai TJ, Brownfield DG, Krasnow MA. Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature. 2014;507:190-194.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 615]  [Cited by in F6Publishing: 654]  [Article Influence: 65.4]  [Reference Citation Analysis (0)]
44.  Liu J, Peng D, You J, Zhou O, Qiu H, Hao C, Chen H, Fu Z, Zou L. Type 2 Alveolar Epithelial Cells Differentiated from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Mouse Pulmonary Fibrosis Through β-Catenin-Regulated Cell Apoptosis. Stem Cells Dev. 2021;30:660-670.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 6]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
45.  Chen XY, Chen KY, Feng PH, Lee KY, Fang YT, Chen YY, Lo YC, Bhavsar PK, Chung KF, Chuang HC. YAP-regulated type II alveolar epithelial cell differentiation mediated by human umbilical cord-derived mesenchymal stem cells in acute respiratory distress syndrome. Biomed Pharmacother. 2023;159:114302.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 5]  [Reference Citation Analysis (0)]
46.  Zhou O, You J, Xu X, Liu J, Qiu H, Hao C, Zou W, Wu W, Fu Z, Tian D, Zou L. Microvesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Enhance Alveolar Type II Cell Proliferation and Attenuate Lung Inflammation in a Rat Model of Bronchopulmonary Dysplasia. Stem Cells Int. 2022;2022:8465294.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 6]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
47.  Wang W, Lei W, Jiang L, Gao S, Hu S, Zhao ZG, Niu CY, Zhao ZA. Therapeutic mechanisms of mesenchymal stem cells in acute respiratory distress syndrome reveal potentials for Covid-19 treatment. J Transl Med. 2021;19:198.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 10]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
48.  Chen L, Qu J, Kalyani FS, Zhang Q, Fan L, Fang Y, Li Y, Xiang C. Mesenchymal stem cell-based treatments for COVID-19: status and future perspectives for clinical applications. Cell Mol Life Sci. 2022;79:142.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 19]  [Article Influence: 9.5]  [Reference Citation Analysis (0)]
49.  Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S, Boyd R, Trounson A. Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Pathol. 2009;175:303-313.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 259]  [Cited by in F6Publishing: 263]  [Article Influence: 17.5]  [Reference Citation Analysis (0)]
50.  Chu KA, Wang SY, Yeh CC, Fu TW, Fu YY, Ko TL, Chiu MM, Chen TH, Tsai PJ, Fu YS. Reversal of bleomycin-induced rat pulmonary fibrosis by a xenograft of human umbilical mesenchymal stem cells from Wharton's jelly. Theranostics. 2019;9:6646-6664.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 47]  [Article Influence: 9.4]  [Reference Citation Analysis (0)]
51.  Tang Z, Gao J, Wu J, Zeng G, Liao Y, Song Z, Liang X, Hu J, Hu Y, Liu M, Li N. Human umbilical cord mesenchymal stromal cells attenuate pulmonary fibrosis via regulatory T cell through interaction with macrophage. Stem Cell Res Ther. 2021;12:397.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 16]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
52.  Khajvand-Abedini M, Bahmani M, Ziamajidi N, Nourian A, Habibi P, Heidarisasan S, Abbasalipourkabir R. The Restoring Effect of Human Umbilical Cord-Derived Mesenchymal Cell-Conditioned Medium (hMSC-CM) against Carbon Tetrachloride-Induced Pulmonary Fibrosis in Male Wistar Rats. Int J Inflam. 2022;2022:7179766.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
53.  Wang Y, Zhang L, Wu Y, Zhu R, Wang Y, Cao Y, Long W, Ji C, Wang H, You L. Peptidome analysis of umbilical cord mesenchymal stem cell (hUC-MSC) conditioned medium from preterm and term infants. Stem Cell Res Ther. 2020;11:414.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 3]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
54.  Alcayaga-Miranda F, Cuenca J, Martin A, Contreras L, Figueroa FE, Khoury M. Combination therapy of menstrual derived mesenchymal stem cells and antibiotics ameliorates survival in sepsis. Stem Cell Res Ther. 2015;6:199.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 85]  [Cited by in F6Publishing: 102]  [Article Influence: 11.3]  [Reference Citation Analysis (0)]
55.  Fernández-Francos S, Eiro N, González-Galiano N, Vizoso FJ. Mesenchymal Stem Cell-Based Therapy as an Alternative to the Treatment of Acute Respiratory Distress Syndrome: Current Evidence and Future Perspectives. Int J Mol Sci. 2021;22.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 29]  [Article Influence: 9.7]  [Reference Citation Analysis (0)]
56.  Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee JW, Matthay MA. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010;28:2229-2238.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 538]  [Cited by in F6Publishing: 548]  [Article Influence: 42.2]  [Reference Citation Analysis (0)]
57.  Sung DK, Chang YS, Sung SI, Yoo HS, Ahn SY, Park WS. Antibacterial effect of mesenchymal stem cells against Escherichia coli is mediated by secretion of beta- defensin- 2 via toll- like receptor 4 signalling. Cell Microbiol. 2016;18:424-436.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 101]  [Cited by in F6Publishing: 108]  [Article Influence: 12.0]  [Reference Citation Analysis (0)]
58.  Ren Z, Zheng X, Yang H, Zhang Q, Liu X, Zhang X, Yang S, Xu F, Yang J. Human umbilical-cord mesenchymal stem cells inhibit bacterial growth and alleviate antibiotic resistance in neonatal imipenem-resistant Pseudomonas aeruginosa infection. Innate Immun. 2020;26:215-221.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 9]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
59.  Horie S, Masterson C, Brady J, Loftus P, Horan E, O'Flynn L, Elliman S, Barry F, O'Brien T, Laffey JG, O'Toole D. Umbilical cord-derived CD362(+) mesenchymal stromal cells for E. coli pneumonia: impact of dose regimen, passage, cryopreservation, and antibiotic therapy. Stem Cell Res Ther. 2020;11:116.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 20]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
60.  Varkouhi AK, Jerkic M, Ormesher L, Gagnon S, Goyal S, Rabani R, Masterson C, Spring C, Chen PZ, Gu FX, Dos Santos CC, Curley GF, Laffey JG. Extracellular Vesicles from Interferon-γ-primed Human Umbilical Cord Mesenchymal Stromal Cells Reduce Escherichia coli-induced Acute Lung Injury in Rats. Anesthesiology. 2019;130:778-790.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 65]  [Article Influence: 16.3]  [Reference Citation Analysis (0)]
61.  Bourgonje AR, Abdulle AE, Timens W, Hillebrands JL, Navis GJ, Gordijn SJ, Bolling MC, Dijkstra G, Voors AA, Osterhaus AD, van der Voort PH, Mulder DJ, van Goor H. Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol. 2020;251:228-248.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 661]  [Cited by in F6Publishing: 636]  [Article Influence: 159.0]  [Reference Citation Analysis (0)]
62.  Shi L, Wang L, Xu R, Zhang C, Xie Y, Liu K, Li T, Hu W, Zhen C, Wang FS. Mesenchymal stem cell therapy for severe COVID-19. Signal Transduct Target Ther. 2021;6:339.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 45]  [Article Influence: 15.0]  [Reference Citation Analysis (0)]
63.  Zhu Q, Xu Y, Wang T, Xie F. Innate and adaptive immune response in SARS-CoV-2 infection-Current perspectives. Front Immunol. 2022;13:1053437.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
64.  Zhang LS, Yu Y, Yu H, Han ZC. Therapeutic prospects of mesenchymal stem/stromal cells in COVID-19 associated pulmonary diseases: From bench to bedside. World J Stem Cells. 2021;13:1058-1071.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 4]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
65.  Jeong YJ, Wi YM, Park H, Lee JE, Kim SH, Lee KS. Current and Emerging Knowledge in COVID-19. Radiology. 2023;306:e222462.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 26]  [Article Influence: 26.0]  [Reference Citation Analysis (0)]
66.  Panahi Y, Gorabi AM, Talaei S, Beiraghdar F, Akbarzadeh A, Tarhriz V, Mellatyar H. An overview on the treatments and prevention against COVID-19. Virol J. 2023;20:23.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 15]  [Reference Citation Analysis (0)]
67.  Zanza C, Romenskaya T, Manetti AC, Franceschi F, La Russa R, Bertozzi G, Maiese A, Savioli G, Volonnino G, Longhitano Y. Cytokine Storm in COVID-19: Immunopathogenesis and Therapy. Medicina (Kaunas). 2022;58.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 98]  [Article Influence: 49.0]  [Reference Citation Analysis (0)]
68.  Weiss ARR, Dahlke MH. Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs. Front Immunol. 2019;10:1191.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 287]  [Cited by in F6Publishing: 401]  [Article Influence: 80.2]  [Reference Citation Analysis (0)]
69.  Niknam Z, Jafari A, Golchin A, Danesh Pouya F, Nemati M, Rezaei-Tavirani M, Rasmi Y. Potential therapeutic options for COVID-19: an update on current evidence. Eur J Med Res. 2022;27:6.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 67]  [Article Influence: 33.5]  [Reference Citation Analysis (0)]
70.  Rebelatto CLK, Senegaglia AC, Franck CL, Daga DR, Shigunov P, Stimamiglio MA, Marsaro DB, Schaidt B, Micosky A, de Azambuja AP, Leitão CA, Petterle RR, Jamur VR, Vaz IM, Mallmann AP, Carraro Junior H, Ditzel E, Brofman PRS, Correa A. Safety and long-term improvement of mesenchymal stromal cell infusion in critically COVID-19 patients: a randomized clinical trial. Stem Cell Res Ther. 2022;13:122.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 17]  [Article Influence: 8.5]  [Reference Citation Analysis (0)]
71.  Tian S, Chang Z, Wang Y, Wu M, Zhang W, Zhou G, Zou X, Tian H, Xiao T, Xing J, Chen J, Han J, Ning K, Wu T. Clinical Characteristics and Reasons for Differences in Duration From Symptom Onset to Release From Quarantine Among Patients With COVID-19 in Liaocheng, China. Front Med (Lausanne). 2020;7:210.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 22]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
72.  Tian H, Sui Y, Tian S, Zou X, Xu Z, He H, Wu T. Case Report: Clinical Treatment of the First Critical Patient With Coronavirus Disease (COVID-19) in Liaocheng, Shandong Province. Front Med (Lausanne). 2020;7:249.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 4]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
73.  Fan S, Wu M, Ma S, Zhao S. A Preventive and Control Strategy for COVID-19 Infection: An Experience From a Third-Tier Chinese City. Front Public Health. 2020;8:562024.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 5]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
74.  Wang Y, Yu J, Wang F, Zhang Y, Ma S. COVID-19 epidemic phases and morbidity in different areas of Chinese mainland, 2020. Front Public Health. 2023;11:1151038.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (1)]
75.  Zhang Y, Ding J, Ren S, Wang W, Yang Y, Li S, Meng M, Wu T, Liu D, Tian S, Tian H, Chen S, Zhou C. Intravenous infusion of human umbilical cord Wharton's jelly-derived mesenchymal stem cells as a potential treatment for patients with COVID-19 pneumonia. Stem Cell Res Ther. 2020;11:207.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 92]  [Cited by in F6Publishing: 86]  [Article Influence: 21.5]  [Reference Citation Analysis (0)]
76.  Qin H, Zhao A. Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics. Protein Cell. 2020;11:707-722.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 78]  [Article Influence: 19.5]  [Reference Citation Analysis (0)]
77.  Kuperminc E, Heming N, Carlos M, Annane D. Corticosteroids in ARDS. J Clin Med. 2023;12.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
78.  Sohni A, Verfaillie CM. Mesenchymal stem cells migration homing and tracking. Stem Cells Int. 2013;2013:130763.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 248]  [Cited by in F6Publishing: 277]  [Article Influence: 25.2]  [Reference Citation Analysis (0)]
79.  Szydlak R. Mesenchymal stem cells' homing and cardiac tissue repair. Acta Biochim Pol. 2019;66:483-489.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 10]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
80.  Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Semprun-Prieto L, Delafontaine P, Prockop DJ. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009;5:54-63.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1329]  [Cited by in F6Publishing: 1353]  [Article Influence: 90.2]  [Reference Citation Analysis (0)]
81.  Kaffash Farkhad N, Sedaghat A, Reihani H, Adhami Moghadam A, Bagheri Moghadam A, Khadem Ghaebi N, Khodadoust MA, Ganjali R, Tafreshian AR, Tavakol-Afshari J. Mesenchymal stromal cell therapy for COVID-19-induced ARDS patients: a successful phase 1, control-placebo group, clinical trial. Stem Cell Res Ther. 2022;13:283.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 18]  [Article Influence: 9.0]  [Reference Citation Analysis (0)]
82.  Monsel A, Hauw-Berlemont C, Mebarki M, Heming N, Mayaux J, Nguekap Tchoumba O, Diehl JL, Demoule A, Annane D, Marois C, Demeret S, Weiss E, Voiriot G, Fartoukh M, Constantin JM, Mégarbane B, Plantefève G, Malard-Castagnet S, Burrel S, Rosenzwajg M, Tchitchek N, Boucher-Pillet H, Churlaud G, Cras A, Maheux C, Pezzana C, Diallo MH, Ropers J, Menasché P, Larghero J; APHP STROMA–CoV-2 Collaborative Research Group. Treatment of COVID-19-associated ARDS with mesenchymal stromal cells: a multicenter randomized double-blind trial. Crit Care. 2022;26:48.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 41]  [Article Influence: 20.5]  [Reference Citation Analysis (0)]
83.  Yip HK, Fang WF, Li YC, Lee FY, Lee CH, Pei SN, Ma MC, Chen KH, Sung PH, Lee MS. Human Umbilical Cord-Derived Mesenchymal Stem Cells for Acute Respiratory Distress Syndrome. Crit Care Med. 2020;48:e391-e399.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 55]  [Article Influence: 18.3]  [Reference Citation Analysis (0)]
84.  Cutz E, Chiasson D. Chronic lung disease after premature birth. N Engl J Med. 2008;358:743-5; author reply 745.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 44]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
85.  McEvoy CT, Spindel ER. Pulmonary Effects of Maternal Smoking on the Fetus and Child: Effects on Lung Development, Respiratory Morbidities, and Life Long Lung Health. Paediatr Respir Rev. 2017;21:27-33.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 108]  [Article Influence: 15.4]  [Reference Citation Analysis (0)]
86.  Alvira CM, Morty RE. Can We Understand the Pathobiology of Bronchopulmonary Dysplasia? J Pediatr. 2017;190:27-37.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 35]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
87.  Liebowitz M, Clyman RI. Prophylactic Indomethacin Compared with Delayed Conservative Management of the Patent Ductus Arteriosus in Extremely Preterm Infants: Effects on Neonatal Outcomes. J Pediatr. 2017;187:119-126.e1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 71]  [Article Influence: 10.1]  [Reference Citation Analysis (0)]
88.  Torchin H, Ancel PY, Goffinet F, Hascoët JM, Truffert P, Tran D, Lebeaux C, Jarreau PH. Placental Complications and Bronchopulmonary Dysplasia: EPIPAGE-2 Cohort Study. Pediatrics. 2016;137:e20152163.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 41]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
89.  Collins JJP, Tibboel D, de Kleer IM, Reiss IKM, Rottier RJ. The Future of Bronchopulmonary Dysplasia: Emerging Pathophysiological Concepts and Potential New Avenues of Treatment. Front Med (Lausanne). 2017;4:61.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 58]  [Article Influence: 8.3]  [Reference Citation Analysis (0)]
90.  Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, Laptook AR, Sánchez PJ, Van Meurs KP, Wyckoff M, Das A, Hale EC, Ball MB, Newman NS, Schibler K, Poindexter BB, Kennedy KA, Cotten CM, Watterberg KL, D'Angio CT, DeMauro SB, Truog WE, Devaskar U, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA. 2015;314:1039-1051.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1793]  [Cited by in F6Publishing: 1714]  [Article Influence: 190.4]  [Reference Citation Analysis (0)]
91.  Dankhara N, Holla I, Ramarao S, Kalikkot Thekkeveedu R. Bronchopulmonary Dysplasia: Pathogenesis and Pathophysiology. J Clin Med. 2023;12.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 2]  [Reference Citation Analysis (0)]
92.  Yazici A, Buyuktiryaki M, Simsek GK, Kanmaz Kutman HG, Canpolat FE. Factors associated with neurodevelopmental impairment in preterm infants with bronchopulmonary dysplasia. Eur Rev Med Pharmacol Sci. 2022;26:1579-1585.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
93.  Fang X, Neyrinck AP, Matthay MA, Lee JW. Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1. J Biol Chem. 2010;285:26211-26222.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 201]  [Cited by in F6Publishing: 203]  [Article Influence: 14.5]  [Reference Citation Analysis (0)]
94.  Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol. 2007;179:1855-1863.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 683]  [Cited by in F6Publishing: 681]  [Article Influence: 40.1]  [Reference Citation Analysis (0)]
95.  Moreira A, Winter C, Joy J, Winter L, Jones M, Noronha M, Porter M, Quim K, Corral A, Alayli Y, Seno T, Mustafa S, Hornsby P, Ahuja S. Intranasal delivery of human umbilical cord Wharton's jelly mesenchymal stromal cells restores lung alveolarization and vascularization in experimental bronchopulmonary dysplasia. Stem Cells Transl Med. 2020;9:221-234.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 23]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
96.  Chang YS, Ahn SY, Yoo HS, Sung SI, Choi SJ, Oh WI, Park WS. Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial. J Pediatr. 2014;164:966-972.e6.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 290]  [Cited by in F6Publishing: 291]  [Article Influence: 29.1]  [Reference Citation Analysis (0)]
97.  Powell SB, Silvestri JM. Safety of Intratracheal Administration of Human Umbilical Cord Blood Derived Mesenchymal Stromal Cells in Extremely Low Birth Weight Preterm Infants. J Pediatr. 2019;210:209-213.e2.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 67]  [Article Influence: 13.4]  [Reference Citation Analysis (0)]
98.  Halpin DMG, Criner GJ, Papi A, Singh D, Anzueto A, Martinez FJ, Agusti AA, Vogelmeier CF. Global Initiative for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease. The 2020 GOLD Science Committee Report on COVID-19 and Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2021;203:24-36.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 339]  [Cited by in F6Publishing: 351]  [Article Influence: 117.0]  [Reference Citation Analysis (0)]
99.  Hashemi SY, Momenabadi V, Faramarzi A, Kiani A. Trends in burden of chronic obstructive pulmonary disease in Iran, 1995-2015: findings from the global burden of disease study. Arch Public Health. 2020;78:45.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 20]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
100.  Vogelmeier CF, Criner GJ, Martínez FJ, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Chen R, Decramer M, Fabbri LM, Frith P, Halpin DM, López Varela MV, Nishimura M, Roche N, Rodríguez-Roisin R, Sin DD, Singh D, Stockley R, Vestbo J, Wedzicha JA, Agustí A. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary. Arch Bronconeumol. 2017;53:128-149.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 215]  [Cited by in F6Publishing: 259]  [Article Influence: 37.0]  [Reference Citation Analysis (0)]
101.  Kume H, Hojo M, Hashimoto N. Eosinophil Inflammation and Hyperresponsiveness in the Airways as Phenotypes of COPD, and Usefulness of Inhaled Glucocorticosteroids. Front Pharmacol. 2019;10:765.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 8]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
102.  Benjamin JT, Plosa EJ, Sucre JM, van der Meer R, Dave S, Gutor S, Nichols DS, Gulleman PM, Jetter CS, Han W, Xin M, Dinella PC, Catanzarite A, Kook S, Dolma K, Lal CV, Gaggar A, Blalock JE, Newcomb DC, Richmond BW, Kropski JA, Young LR, Guttentag SH, Blackwell TS. Neutrophilic inflammation during lung development disrupts elastin assembly and predisposes adult mice to COPD. J Clin Invest. 2021;131.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 34]  [Article Influence: 11.3]  [Reference Citation Analysis (0)]
103.  Kahnert K, Jörres RA, Behr J, Welte T. The Diagnosis and Treatment of COPD and Its Comorbidities. Dtsch Arztebl Int. 2023;120:434-444.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
104.  Ferri S, Paoletti G, Pelaia C, Heffler E, Canonica GW, Puggioni F. COPD and biologic treatment: state of the art. Curr Opin Allergy Clin Immunol. 2023;23:309-318.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
105.  Cruz FF, Rocco PRM. The potential of mesenchymal stem cell therapy for chronic lung disease. Expert Rev Respir Med. 2020;14:31-39.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 93]  [Article Influence: 18.6]  [Reference Citation Analysis (0)]
106.  Río C, Jahn AK, Martin-Medina A, Calvo Bota AM, De Francisco Casado MT, Pont Antona PJ, Gigirey Castro O, Carvajal ÁF, Villena Portella C, Gómez Bellvert C, Iglesias A, Calvo Benito J, Gayà Puig A, Ortiz LA, Sala-Llinàs E. Mesenchymal Stem Cells from COPD Patients Are Capable of Restoring Elastase-Induced Emphysema in a Murine Experimental Model. Int J Mol Sci. 2023;24.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
107.  Zhang C, Zhao H, Li BL, Liu H, Cai JM, Zheng M. CpG-oligodeoxynucleotides may be effective for preventing ionizing radiation induced pulmonary fibrosis. Toxicol Lett. 2018;292:181-189.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 12]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
108.  Piotrowski WJ, Bestry I, Białas AJ, Boros PW, Grzanka P, Jassem E, Jastrzębski D, Klimczak D, Langfort R, Lewandowska K, Majewski S, Martusewicz-Boros MM, Onisch K, Puścińska E, Siemińska A, Sobiecka M, Szołkowska M, Wiatr E, Wilczyński G, Ziora D, Kuś J. Guidelines of the Polish Respiratory Society for diagnosis and treatment of idiopathic pulmonary fibrosis. Adv Respir Med. 2020;88:41-93.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 16]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
109.  De Matteis S, Murgia N. Work-related interstitial lung disease: what is the true burden? Int J Tuberc Lung Dis. 2022;26:1001-1005.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
110.  Andreikos D, Karampitsakos T, Tzouvelekis A, Stratakos G. Statins' still controversial role in pulmonary fibrosis: What does the evidence show? Pulm Pharmacol Ther. 2022;77:102168.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
111.  Chuang HM, Shih TE, Lu KY, Tsai SF, Harn HJ, Ho LI. Mesenchymal Stem Cell Therapy of Pulmonary Fibrosis: Improvement with Target Combination. Cell Transplant. 2018;27:1581-1587.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 35]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
112.  Toonkel RL, Hare JM, Matthay MA, Glassberg MK. Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing. Am J Respir Crit Care Med. 2013;188:133-140.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 88]  [Cited by in F6Publishing: 97]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
113.  Tzouvelekis A, Toonkel R, Karampitsakos T, Medapalli K, Ninou I, Aidinis V, Bouros D, Glassberg MK. Mesenchymal Stem Cells for the Treatment of Idiopathic Pulmonary Fibrosis. Front Med (Lausanne). 2018;5:142.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 45]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
114.  Guo Z, Zhang Y, Yan F. Potential of Mesenchymal Stem Cell-Based Therapies for Pulmonary Fibrosis. DNA Cell Biol. 2022;41:951-965.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
115.  Worthington EN, Hagood JS. Therapeutic Use of Extracellular Vesicles for Acute and Chronic Lung Disease. Int J Mol Sci. 2020;21.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 57]  [Article Influence: 14.3]  [Reference Citation Analysis (0)]
116.  Saleh M, Fotook Kiaei SZ, Kavianpour M. Application of Wharton jelly-derived mesenchymal stem cells in patients with pulmonary fibrosis. Stem Cell Res Ther. 2022;13:71.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
117.  da Silva KN, Pinheiro PCG, Gobatto ALN, Passos RDH, Paredes BD, França LSA, Nonaka CKV, Barreto-Duarte B, Araújo-Pereira M, Tibúrcio R, Cruz FF, Martins GLS, Andrade BB, de Castro-Faria-Neto HC, Rocco PRM, Souza BSF. Immunomodulatory and Anti-fibrotic Effects Following the Infusion of Umbilical Cord Mesenchymal Stromal Cells in a Critically Ill Patient With COVID-19 Presenting Lung Fibrosis: A Case Report. Front Med (Lausanne). 2021;8:767291.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]