• Acute respiratory distress syndrome
• Inflammatory response
• Mesenchymal stem cells
• Pulmonary edema
• Pulmonary fibrosis
• Tissue repair

Mesenchymal stromal cells (MSCs) transplantation showed promising therapeutic results in liver fibrosis. However, efficient cell delivery method is urgently needed and the therapeutic mechanism remains unclear. This study focused on developing a minimally invasive open-flow microperfusion (OFM) technique, which combined orthotopic transplantation of human umbilical cord-derived (hUC)-MSCs to liver and in vivo monitoring of liver microenvironment in mice with CCl₄-induced liver fibrosis.

The therapeutic potential of OFM route was evaluated by comparing OFM with intravenous (IV) injection route in terms of hUC-MSCs engraftment at the fibrosis liver, liver histopathological features, liver function and fibrotic markers expression after hUC-MSCs administration. OFM was also applied to sample liver interstitial fluid in vivo, and subsequent metabolomic analysis was performed to investigate metabolic changes in liver microenvironment.

Compared with IV route, OFM route caused more hUC-MSCs accumulation in the liver and was more effective in improving the remodeling of liver structure and reducing collagen deposition in fibrotic liver. OFM transplantation of hUC-MSCs reduced blood ALT, AST, ALP and TBIL levels and increased ALB levels, to a greater extent than IV route. And OFM route appeared to have a more pronounced effect on ameliorating the CCl₄-induced up-regulation of the fibrotic markers, such as α-SMA, collagen I and TGF-β. In vivo monitoring of liver microenvironment demonstrated the metabolic perturbations induced by pathological condition and treatment intervention. Two metabolites and eight metabolic pathways, which were most likely to be associated with the liver fibrosis progression, were regulated by hUC-MSCs administration.

The results demonstrated that the novel OFM technique would be useful for hUC-MSCs transplantation in liver fibrosis treatment and for monitoring of the liver metabolic microenvironment to explore the underlying therapeutic mechanisms.

The online version contains supplementary material available at 10.1186/s13287-021-02599-w.

• Liver fibrosis
• Metabolomics
• Microenvironment
• Open-flow microperfusion
• Orthotopic transplantation
• Umbilical cord mesenchymal stem cells

Mesenchymal stromal cell (MSC) therapy is a potential therapy for treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), which was widely studied in the last decade. The purpose of our meta-analysis was to investigate the efficacy of MSCs for simulated infection-induced ALI/ARDS in animal trials. PubMed and EMBASE were searched to screen relevant preclinical trials with a prespecified search strategy. 57 studies met the inclusion criteria and were included in our study. Our meta-analysis showed that MSCs can reduce the lung injury score of ALI caused by lipopolysaccharide or bacteria (standardized mean difference (SMD) = −2.97, 95% CI [−3.64 to −2.30], P < 0.00001) and improve the animals’ survival (odds ratio = 3.64, 95% CI [2.55 to 5.19], P < 0.00001). Our study discovered that MSCs can reduce the wet weight to dry weight ratio of the lung (SMD = −2.58, 95% CI [−3.24 to −1.91], P < 0.00001). The proportion of the alveolar sac in the MSC group was higher than that in the control group (SMD = 1.68, 95% CI [1.22 to 2.13], P < 0.00001). Moreover, our study detected that MSCs can downregulate the levels of proinflammatory factors such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the lung and it can upregulate the level of anti-inflammatory factor IL-10. MSCs were also found to reduce the level of neutrophils and total protein in bronchoalveolar lavage fluid, decrease myeloperoxidase (MPO) activity in the lung, and improve lung compliance. MSC therapy may be a promising treatment for ALI/ARDS since it may mitigate the severity of lung injury, modulate the immune balance, and ameliorate the permeability of lung vessels in ALI/ARDS, thus facilitating lung regeneration and repair.

• acute lung injury
• acute respiratory distress syndrome
• cell therapy
• mesenchymal stromal cell
• stem cell

The therapeutic value of mesenchymal stem cells (MSCs) for the treatment of infectious diseases and the repair of disease-induced tissue damage has been explored extensively. MSCs inhibit inflammation, reduce pathogen load and tissue damage encountered during infectious diseases through the secretion of antimicrobial factors for pathogen clearance and they phagocytose certain bacteria themselves. MSCs dampen tissue damage during infection by downregulating the levels of pro-inflammatory cytokines, and inhibiting the excessive recruitment of neutrophils and proliferation of T cells at the site of injury. MSCs aid in the regeneration of damaged tissue by differentiating into the damaged cell types or by releasing paracrine factors that direct tissue regeneration, differentiation, and wound healing. In this review, we discuss in detail the various mechanisms by which MSCs help combat pathogens, tissue damage associated with infectious diseases, and challenges in utilizing MSCs for therapy.

• Infectious diseases
• Mesenchymal stem cells
• Antimicrobial effect
• Immunomodulation
• Tissue repair
• COVID-19

• adipose tissue stromal cells (atMSCs)
• bone marrow MSCs (bmMSC)
• cell-based immune modulation
• mesenchymal stromal/stem cells (MSC)
• placenta-derived mesenchymal stromal cells (hPSCs/pMSCs)
• pro-regenerative effects
• regenerative cell therapy
• xenogeneic cell delivery

• Adipose Tissue/metabolism
• Allografts/metabolism
• Animals
• Bone Marrow/metabolism
• Bone Marrow Cells/metabolism
• Cell Differentiation/physiology
• Cell Proliferation/physiology
• Cell- and Tissue-Based Therapy/methods
• Female
• Humans
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/metabolism
• Placenta/metabolism
• Placenta/physiology
• Pregnancy
• Stromal Cells/metabolism

• 1639/14 Israel Science Foundation

• acute pancreatitis
• chronic pancreatitis
• mesenchymal stromal cell

• Airway injury
• ERK1/2
• epithelial sodium channel
• mesenchymal stem cells-conditioned medium
• mouse tracheal epithelial cells
• with-nolysine- kinase-4

Acute lung injury (ALI) is a pulmonary disorder, which can result in fibrosis of the lung tissues. Recently, mesenchymal stem cell (MSC) has become a novel therapeutic method for ALI. However, the potential mechanism by which MSC regulates the progression of ALI remains blurry. The present study focused on investigating the mechanism underneath MSC-reversed lung injury and fibrosis. At first, we determined that coculture with MSC led to the inactivation of NF-κB signaling and therefore suppressed hedgehog pathway in LPS-treated MLE-12 cells. Besides, we confirmed that MSC-exosomes were responsible for the inhibition of EMT process in LPS-treated MLE-12 cells through transmitting miRNAs. Mechanism investigation revealed that MSC-exosome transmitted miR-182-5p and miR-23a-3p into LPS-treated MLE-12 cells to, respectively, target Ikbkb and Usp5. Of note, Usp5 interacted with IKKβ to hamper IKKβ ubiquitination. Moreover, co-inhibition of miR-182-5p and miR-23a-3p offset the suppression of MSC on EMT process in LPS-treated MLE-12 cells as well as in LPS-injured lungs of mice. Besides, the retarding effect of MSC on p65 nuclear translocation was also counteracted after co-inhibiting miR-182-5p and miR-23a-3p, both in vitro and in vivo. In summary, MSC-exosome transmitted miR-23a-3p and miR-182-5p reversed the progression of LPS-induced lung injury and fibrosis through inhibiting NF-κB and hedgehog pathways via silencing Ikbkb and destabilizing IKKβ.

Cigarette smoke (CS) has been reported to induce oxidative stress and inflammatory process in the lungs. However, the role of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in the regulation of pulmonary inflammation remains unclear. The objective of this study is to investigate the effects of hUC-MSCs on lung inflammation in the acute CS-induced pulmonary inflammation animal model. Eight-week-old male C57BL/6 mice were intravenously administered 3 × 10⁶, 1 × 10⁷, and 3 × 10⁷ cells/kg of hUC-MSCs as well as normal saline alone (control) after 3 days of CS exposure. Mice exposed to high-efficiency particulate air (HEPA)-filtered room air served as the CS control group. High-dose (3 × 10⁷ cells/kg) hUC-MSC administration significantly decreased tumor necrosis factor (TNF)-α in the bronchoalveolar lavage fluid (BALF) of CS-exposed mice (p < 0.05). The chemokine (CXC motif) ligand 1/keratinocyte chemoattractant (CXCL1/KC) in BALF were significantly reduced by low-dose (3 × 10⁶ cells/kg) and high-dose (3 × 10⁷ cells/kg) hUC-MSC (p < 0.05). Medium-dose hUC-MSC administration decreased interleukin (IL)-1β in lung of mice, and TNF-α and caspase-3 were decreased in the lung of CS-exposed mice by medium- and high-dose MSC (p < 0.05). Low-dose hUC-MSCs significantly elevated serum CXCL1/KC and IL-1β in CS-exposed mice (p < 0.05). Our results suggest that high-dose hUC-MSCs reduced pulmonary inflammation and had antiapoptotic effects in acute pulmonary inflammation.

• cigarette smoke
• inflammation
• lung
• mesenchymal stem cells
• oxidative stress

• Acute lung injury
• Cecal ligation and puncture
• Gut microbiota
• Mesenchymal stem cells
• Sepsis

• Acute Lung Injury/therapy
• Animals
• Gastrointestinal Microbiome
• Interleukin-6
• Lung
• Male
• Mesenchymal Stem Cells
• Rats
• Rats, Sprague-Dawley
• Sepsis/therapy
• Tumor Necrosis Factor-alpha

• the Scientific and Technological Innovation leaders in Central Plains
• Provincial Ministry Co-construction Project from Medical Scientific and Technological Research Program of Henan Province

• Angiogenesis
• Apoptosis
• Mesenchymal stem cells
• Resveratrol
• Severe acute pancreatitis
• Vascular endothelial growth factor

• Acute lung injury (ALI)
• Acute respiratory distress syndrome (ARDS)
• Akt
• Dendritic cells
• Hepatocyte growth factor (HGF)
• Mesenchymal stem cell (MSC)

• Acute lung injury
• Alveolar epithelial cells
• Exosome
• Mesenchymal stem cells
• Serum amyloid A3
• microRNA-30b-3p

• Anti-inflammatory
• Antioxidant
• BMSCs
• NAC
• SAP

• airway injury
• bronchiolar epithelial cell
• mesenchymal stem cell
• naphthalene
• regeneration

• Acute respiratory distress syndrome (ARDS)
• cell therapy
• mesenchymal stromal cells (MSCs)

Although mesenchymal stem cells (MSCs) transplantation has been shown to promote the lung respiration in acute lung injury (ALI) in vivo, its overall restorative capacity appears to be restricted mainly because of low retention in the injured lung. Angiotensin II (Ang II) are upregulated in the injured lung. Our previous study showed that Ang II increased MSCs migration via Ang II type 2 receptor (AT2R). To determine the effect of AT2R in MSCs on their cell migration after systemic injection in ALI mice, a human AT2R expressing lentiviral vector and a lentivirus vector carrying AT2R shRNA were constructed and introduced into human bone marrow MSCs. A mouse model of lipopolysaccharide‐induced ALI was used to investigate the migration of AT2R‐regulated MSCs and the therapeutic potential in vivo. Overexpression of AT2R dramatically increased Ang II‐enhanced human bone marrow MSC migration in vitro. Moreover, MSC‐AT2R accumulated in the damaged lung tissue at significantly higher levels than control MSCs 24 and 72 hours after systematic MSC transplantation in ALI mice. Furthermore, MSC‐AT2R‐injected ALI mice exhibited a significant reduction of pulmonary vascular permeability and improved the lung histopathology and had additional anti‐inflammatory effects. In contrast, there were less lung retention in MSC‐ShAT2R‐injected ALI mice compared with MSC‐Shcontrol after transplantation. Thus, MSC‐ShAT2R‐injected group exhibited a significant increase of pulmonary vascular permeability and resulted in a deteriorative lung inflammation. Our results demonstrate that overexpression of AT2R enhance the migration of MSCs in ALI mice and may provide a new therapeutic strategy for ALI. Stem Cells Translational Medicine2018;7:721–730

• AT2R
• Acute lung injury
• Lentiviral vector
• Mesenchymal stem cells
• Migration

The aim of the present study was topreliminarily visualize the distribution of humanumbilical cord-derived-mesenchymal stem cells (hUC-MSCs) in treating acute lung injury (ALI) using a targeted fluorescent technique. Anovel fluorescent molecule probe was first synthesized via the specific binding of antigen and antibody in vitro to label the hUC-MSCs. Two groups of mice, comprising a normal saline (NS)+MSC group and lipopolysaccharide (LPS)+MSC group, were subjected to optical imaging. At 4 h following ALI mouse model construction, the labeled hUC-MSCs were transplanted into the mice in the NS+MSC group and LPS+MSC group by tail vein injection. The mice were sacrificed 30 min, 1 day, 3 days and 7 days following injection of the labeled hUC-MSCs, and the lungs, heart, spleen, kidneys and liver were removed. The excised lungs, heart, spleen, kidneys and liver were then detected on asmall animal fluorescent imager. The fluorescent results showed that the signal intensity in the lungs of the LPS+MSC group was significantly higher, compared with that of the NS+MSC group at 30 min (3.53±0.06×10⁻⁴, vs. 1.95±0.05×10⁻⁴ scaled counts/sec), 1 day (36.20±0.77×10⁻⁴, vs. 23.45±0.43×10⁻⁴ scaled counts/sec), 3 days (11.83±0.26×10⁻⁴, vs. 5.39±0.10×10⁻⁴ scaled counts/sec), and 7 days (3.14±0.04×10⁻⁴, vs. 0.00±0.00×10⁻⁴ scaled counts/sec; all P<0.05). The fluorescence intensity in the liver of the LPS+MSC group, vs. NS+MSC group was measured at 30 min (0.00±0.00×10⁻⁴, vs. 0.00±0.00×10⁻⁴ scaled counts/sec); 1 day (5.53±0.08×10⁻⁴, vs. 5.44±0.16×10⁻⁴ scaled counts/sec); 3 days (0.00±0.00×10⁻⁴, vs. 8.67±0.05×10⁻⁴ scaled counts/sec); 7 days (0.00±0.00×10⁻⁴, vs. 0.00±0.00×10⁻⁴ scaled counts/sec). The signal intensity of the heart, spleen and kidneys was minimal. In conclusion, the novel targeted fluorescence molecular probe was suitable for tracking the distribution processes of hUC-MSCs in treating ALI.

• Extrapulmonary ARDS
• MicroRNA
• Pulmonary ARDS
• Vascular endothelial cell

Radiation therapy is an important treatment modality for multiple thoracic malignancies. However, radiation‐induced lung injury (RILI), which is the term generally used to describe damage to the lungs caused by exposure to ionizing radiation, remains a critical issue affecting both tumor control and patient quality of life. Despite tremendous effort, there is no current consensus regarding the optimal treatment approach for RILI. Because of a number of functional advantages, including self‐proliferation, multi‐differentiation, injury foci chemotaxis, anti‐inflammation, and immunomodulation, mesenchymal stem cells (MSCs) have been a focus of research for many years. Accumulating evidence indicates the therapeutic potential of transplantation of MSCs derived from adipose tissue, umbilical cord blood, and bone marrow for inflammatory diseases, including RILI. However, reports have also shown that MSCs, including fibrocytes, lung hematopoietic progenitor cells, and ABCG²⁺ MSCs, actually enhance the progression of lung injuries. These contradictory results suggest that MSCs may have dual effects and that caution should be taken when using MSCs to treat RILI. In this review, we present and discuss recent evidence of the double‐edged function of MSCs and provide comments on the prospects of these findings.

• Gene modification
• lung injury
• mesenchymal stem cells
• radiation
• transplantation

• hyperglycemia
• inflammatory
• insulin sensitivity
• spleen
• type 2 diabetes

Mesenchymal stem cells microvesicles (MSC-MVs) stabilize endothelial barrier function in acute lung injury (ALI); however, the detailed mechanism remains to be further defined. Hepatocyte growth factor (HGF), which is derived from MSC-MVs, might have a key role in the restoration of endothelial barrier function by MSC-MVs.

MSCs with lentiviral vector-mediated HGF gene knockdown (siHGF-MSC) were generated. A co-culture model of pulmonary microvascular endothelial cells and MSC-MVs collected from MSCs or siHGF-MSCs after 24 h of hypoxic culture was utilized. Then, endothelial paracellular and transcellular permeabilities were detected. VE-cadherin, and occludin protein expression in the endothelial cells was measured using Western blot. Endothelial cell proliferation was analysed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. Endothelial cell apoptosis was analysed using TUNEL assay. Finally, IL-6 and IL-10 production was determined via an enzyme-linked immunosorbent assay (ELISA).

Treatment with MSC-MVs significantly decreased LPS-induced endothelial paracellular and transcellular permeabilities, and the effect was significantly inhibited after HGF gene knockdown in MSC-MVs. Furthermore, treatment with MSC-MVs increased the expression of the endothelial intercellular junction proteins VE-cadherin and occludin. Treatment with MSC-MVs also decreased endothelial apoptosis and induced endothelial cell proliferation. Finally, the treatment reduced IL-6 production and increased IL-10 production in the conditioned media of endothelial cells. However, the effects of the treatment with MSC-MVs were inhibited after HGF gene knockdown.

MSC-MVs protect the barrier functions of pulmonary microvascular endothelial cells, which can be partly attributed to the presence of HGF in the MSC-MVs.

• Acute lung injury
• Endothelial permeability
• Hepatocyte growth factor
• Mesenchymal stem cells microvesicles

Mesenchymal stem cells (MSCs) migrate via the bloodstream to sites of injury and are possibly attracted by inflammatory factors. As a proinflammatory mediator, angiotensin II (Ang II) reportedly enhances the migration of various cell types by signaling via the Ang II receptor in vitro. However, few studies have focused on the effects of Ang II on MSC migration and the underlying mechanisms.

Human bone marrow MSCs migration was measured using wound healing and Boyden chamber migration assays after treatments with different concentrations of Ang II, an AT1R antagonist (Losartan), and/or an AT2R antagonist (PD-123319). To exclude the effect of proliferation on MSC migration, we measured MSC proliferation after stimulation with the same concentration of Ang II. Additionally, we employed the focal adhesion kinase (FAK) inhibitor PF-573228, RhoA inhibitor C3 transferase, Rac1 inhibitor NSC23766, or Cdc42 inhibitor ML141 to investigate the role of cell adhesion proteins and the Rho-GTPase protein family (RhoA, Rac1, and Cdc42) in Ang II-mediated MSC migration. Cell adhesion proteins (FAK, Talin, and Vinculin) were detected by western blot analysis. The Rho-GTPase family protein activities were assessed by G-LISA and F-actin levels, which reflect actin cytoskeletal organization, were detected by using immunofluorescence.

Human bone marrow MSCs constitutively expressed AT1R and AT2R. Additionally, Ang II increased MSC migration in an AT2R-dependent manner. Notably, Ang II-enhanced migration was not mediated by Ang II-mediated cell proliferation. Interestingly, Ang II-enhanced migration was mediated by FAK activation, which was critical for the formation of focal contacts, as evidenced by increased Talin and Vinculin expression. Moreover, RhoA and Cdc42 were activated by FAK to increase cytoskeletal organization, thus promoting cell contraction. Furthermore, FAK, Talin, and Vinculin activation and F-actin reorganization in response to Ang II were prevented by PD-123319 but not Losartan, indicating that FAK activation and F-actin reorganization were downstream of AT2R.

These data indicate that Ang II-AT2R regulates human bone marrow MSC migration by signaling through the FAK and RhoA/Cdc42 pathways. This study provides insights into the mechanisms by which MSCs home to injury sites and will enable the rational design of targeted therapies to improve MSC engraftment.

• AT1R
• AT2R
• Angiotensin II
• Cell migration
• F-actin
• Focal adhesion kinase
• Mesenchymal stem cells
• Rho GTPases

Idiopathic pulmonary fibrosis (IPF) is a major cause of respiratory failure in critically ill patients and common outcome of various lung interstitial diseases. Its mortality remains high, and no effective pharmacotherapy, in addition to artificial ventilation and transplantation, exists. As such, the administration of mesenchymal stem or stromal cells (MSCs) is currently investigated as a new therapeutic method for pulmonary fibrosis. Clinical trials on MSC-based therapy as a potential treatment for lung injury and fibrosis are also performed. MSCs can migrate to injured sites and secrete multiple paracrine factors and then regulate endothelial and epithelial permeability, decrease inflammation, enhance tissue repair, and inhibit bacterial growth. In this review, recent studies on stem cells, particularly MSCs, involved in alleviating lung inflammation and fibrosis and their potential MSC-induced mechanisms, including migration and differentiation, soluble factor and extracellular vesicle secretion, and endogenous regulatory functions, were summarized.

• idiopathic pulmonary fibrosis
• immunomodulation
• mesenchymal stem cells
• mobilization
• secretome

• Acute Lung Injury/drug therapy
• Animals
• Anti-Inflammatory Agents/therapeutic use
• Humans
• Respiratory Distress Syndrome/therapy

• U01 HL123031 NHLBI NIH HHS
• HL123515 NHLBI NIH HHS
• R01 HL123515 NHLBI NIH HHS
• R37 GM029507 NIGMS NIH HHS
• R01 GM029507 NIGMS NIH HHS
• GM29507 NIGMS NIH HHS
• GM61656 NIGMS NIH HHS
• R01 GM061656 NIGMS NIH HHS