• canine cardiology
• cardiac regeneration
• mesenchymal stem cells
• stem cell therapy
• veterinary cardiology

• Dogs
• Animals
• Cardiovascular Diseases/therapy
• Cardiovascular Diseases/veterinary
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cell Transplantation/methods
• Stem Cell Transplantation
• Humans
• Dog Diseases/therapy

• Cystic fibrosis
• Immune therapy
• Infection
• Inflammation
• Mesenchymal stem cells

• Humans
• Cystic Fibrosis/therapy
• Cystic Fibrosis/pathology
• Cystic Fibrosis/genetics
• Cystic Fibrosis/immunology
• Cystic Fibrosis/microbiology
• Cystic Fibrosis/complications
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/immunology
• Mesenchymal Stem Cells/cytology
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
• Cystic Fibrosis Transmembrane Conductance Regulator/immunology
• Animals
• Inflammation/therapy
• Inflammation/pathology

• Humans
• Cell- and Tissue-Based Therapy/methods
• End Stage Liver Disease/therapy
• Hepatocytes
• Mesenchymal Stem Cell Transplantation
• Stem Cell Transplantation

• ADSC
• chronic wounds
• histology
• lipofilling
• microbiology

• Humans
• Wound Healing
• Prospective Studies
• Varicose Ulcer/therapy
• Leg Ulcer/surgery
• Adipose Tissue
• Pain

• Ernst Wendt Family Foundation of the City of Cologne

• chronic liver disease
• extracellular vesicles
• immunomodulation
• mesenchymal stromal cells

• Humans
• Liver Diseases/therapy
• Liver Transplantation
• Cell- and Tissue-Based Therapy
• Immunomodulation
• Mesenchymal Stem Cells
• Extracellular Vesicles
• Mesenchymal Stem Cell Transplantation

• Department of Health
• National institute for Health Research
• University of Birmingham
• department of Health and Social care
• Birmingham Biomedical Research Centre

Diseases caused by ischemia are one of the leading causes of death in the world. Current therapies for treating acute myocardial infarction, ischemic stroke, and critical limb ischemia do not complete recovery. Regenerative therapies opens new therapeutic strategy in the treatment of ischemic disorders. Mesenchymal stem cells (MSCs) are the most promising option in the field of cell-based therapies, due to their secretory and immunomodulatory abilities, that contribute to ease inflammation and promote the regeneration of damaged tissues. This review presents the current knowledge of the mechanisms of action of MSCs and their therapeutic effects in the treatment of ischemic diseases, described on the basis of data from in vitro experiments and preclinical animal studies, and also summarize the effects of using these cells in clinical trial settings. Since the obtained therapeutic benefits are not always satisfactory, approaches aimed at enhancing the effect of MSCs in regenerative therapies are presented at the end.

• Ischemia
• Mesenchymal stem cells
• Regenerative medicine
• Stem cell therapy
• Clinical applications

• anti-inflammatory potency
• anti-microbial potency
• clinical trial development
• cystic fibrosis
• human mesenchymal stem cells

• ABCB5
• advanced-therapy medicinal product
• angiogenesis
• cell therapy
• chronic wound
• epidermolysis bullosa
• immunomodulation
• inflammation
• mesenchymal stem cells
• wound healing

• United States
• Humans
• Mesenchymal Stem Cells/metabolism
• Epidermolysis Bullosa Dystrophica/metabolism
• Germany
• ATP Binding Cassette Transporter, Subfamily B/metabolism

• 1R01HL161087 NHLBI NIH HHS
• R24 EY028767 NEI NIH HHS
• R01 EY025794 NEI NIH HHS
• RO1EY025794 NEI NIH HHS
• P01 AG071463 NIA NIH HHS
• R24EY028767 NEI NIH HHS
• R01 HL161087 NHLBI NIH HHS

While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5⁺ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers.

The angiogenic potential of ABCB5⁺ MSCs was characterized with respect to angiogenic factor expression at the mRNA and protein level, in vitro endothelial trans-differentiation and tube formation potential, and perfusion-restoring capacity in a mouse hindlimb ischemia model. Finally, the efficacy and safety of ABCB5⁺ MSCs for topical adjunctive treatment of chronic, standard therapy-refractory, neuropathic plantar DFUs were assessed in an open-label single-arm clinical trial.

Hypoxic incubation of ABCB5⁺ MSCs led to posttranslational stabilization of the hypoxia-inducible transcription factor 1α (HIF-1α) and upregulation of HIF-1α mRNA levels. HIF-1α pathway activation was accompanied by upregulation of vascular endothelial growth factor (VEGF) transcription and increase in VEGF protein secretion. Upon culture in growth factor-supplemented medium, ABCB5⁺ MSCs expressed the endothelial-lineage marker CD31, and after seeding on gel matrix, ABCB5⁺ MSCs demonstrated formation of capillary-like structures comparable with human umbilical vein endothelial cells. Intramuscularly injected ABCB5⁺ MSCs to mice with surgically induced hindlimb ischemia accelerated perfusion recovery as measured by laser Doppler blood perfusion imaging and enhanced capillary proliferation and vascularization in the ischemic muscles. Adjunctive topical application of ABCB5⁺ MSCs onto therapy-refractory DFUs elicited median wound surface area reductions from baseline of 59% (full analysis set, n = 23), 64% (per-protocol set, n = 20) and 67% (subgroup of responders, n = 17) at week 12, while no treatment-related adverse events were observed.

The present observations identify GMP-manufactured ABCB5⁺ dermal MSCs as a potential, safe candidate for adjunctive therapy of otherwise incurable DFUs and justify the conduct of a larger, randomized controlled trial to validate the clinical efficacy.

Trial registration: ClinicalTrials.gov, NCT03267784, Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT03267784

The online version contains supplementary material available at 10.1186/s13287-022-03156-9.

• ABCB5
• Advanced-therapy medicinal product
• Angiogenesis
• Chronic wound
• Diabetic foot ulcer
• Mesenchymal stem cells
• Wound healing

Regenerative cell therapies, such as adipose-derived stromal vascular fraction (SVF), have been postulated as potential treatments for knee osteoarthritis (KOA).

To assess the efficacy and safety of SVF treatment against placebo and other standard therapies for treating KOA in adult patients.

A systematic review.

We searched the following databases: MEDLINE via PubMed, Epistemonikos, PEDro, DynaMed, TripDatabase, Elsevier via Clinicalkey and Cochrane Controlled Trials Register. We included prospective interventional studies where treatment with SVF in adults with KOA was compared against placebo or other standard therapies, and results were objectively measured with at least one widely recognised osteoarthritis scale.

Among 266 studies published until May 2021, nine met our inclusion criteria. A total of 239 patients (274 knees) were included in our study. The follow-up ranged from 6 to 24 months. Six studies had a control group (only one being placebo). All studies showed that SVF improved pain and functionality measured, in most cases, with the visual analogue scale and the Western Ontario and McMaster Universities Osteoarthritis Index. In addition, five studies reported an improvement in anatomical structures, as detected in MR images. However, the number of cells contained in SVF varied substantially between different studies, which could induce a comparison bias.

Although based on a small number of dissimilar studies, SVF was considered a safe treatment for KOA and could be promising in terms of pain, functionality and anatomical structure improvement. However, SVF products need to be standardised, the number of cells homogenised and the use of concomitant treatments reduced to establish proper comparisons.

PROSPERO registration number: CRD42021284187.

• knee osteoarthritis
• mesenchymal stem cells
• regenerative medicine
• stromal vascular fraction

• cvu, chronic venous ulcer
• fas, full analysis set
• iqr, interquartile range
• msc, mesenchymal stem cell
• pp, per-protocol set
• teae, treatment-emergent adverse event

• R01 EY025794 NEI NIH HHS
• R24 EY028767 NEI NIH HHS

• COVID-19
• discovery research
• translation
•  mesenchymal stem cell

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and life-threatening inherited skin fragility disorder that comes about due to a lack of functional type VII collagen, for which no effective therapy exists. ABCB5⁺ dermal mesenchymal stem cells (ABCB5⁺ MSCs) possess immunomodulatory, inflammation-dampening, and tissue-healing capacities. In a Col7a1^–/– mouse model of RDEB, treatment with ABCB5⁺ MSCs markedly extended the animals’ lifespans.

In this international, multicentric, single-arm, phase I/IIa clinical trial, 16 patients (aged 4–36 years) enrolled into 4 age cohorts received 3 i.v. infusions of 2 × 10⁶ ABCB5⁺ MSCs/kg on days 0, 17, and 35. Patients were followed up for 12 weeks regarding efficacy and 12 months regarding safety.

At 12 weeks, statistically significant median (IQR) reductions in the Epidermolysis Bullosa Disease Activity and Scarring Index activity (EBDASI activity) score of 13.0% (2.9%–30%; P = 0.049) and the Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa clinician (iscorEB‑c) score of 18.2% (1.9%–39.8%; P = 0.037) were observed. Reductions in itch and pain numerical rating scale scores were greatest on day 35, amounting to 37.5% (0.0%–42.9%; P = 0.033) and 25.0% (–8.4% to 46.4%; P = 0.168), respectively. Three adverse events were considered related to the cell product: 1 mild lymphadenopathy and 2 hypersensitivity reactions. The latter 2 were serious but resolved without sequelae shortly after withdrawal of treatment.

This trial demonstrates good tolerability, manageable safety, and potential efficacy of i.v. ABCB5⁺ MSCs as a readily available disease-modifying therapy for RDEB and provides a rationale for further clinical evaluation.

Clinicaltrials.gov NCT03529877; EudraCT 2018-001009-98.

The trial was sponsored by RHEACELL GmbH & Co. KG. Contributions by NYF and MHF to this work were supported by the NIH/National Eye Institute (NEI) grants RO1EY025794 and R24EY028767.

• Adult stem cells
• Clinical Trials
• Stem cells

In cystic fibrosis (CF), sustained infection and exuberant inflammation results in debilitating and often fatal lung disease. Advancement in CF therapeutics has provided successful treatment regimens for a variety of clinical consequences in CF; however effective means to treat the pulmonary infection and inflammation continues to be problematic. Even with the successful development of small molecule cystic fibrosis transmembrane conductance regulator (CFTR) correctors and potentiators, there is only a modest effect on established infection and inflammation in CF patients. In the pursuit of therapeutics to treat inflammation, the conundrum to address is how to overcome the inflammatory response without jeopardizing the required immunity to manage pathogens and prevent infection. The key therapeutic would have the capacity to dull the inflammatory response, while sustaining the ability to manage infections. Advances in cell-based therapy have opened up the avenue for dynamic and versatile immune interventions that may support this requirement. Cell based therapy has the capacity to augment the patient’s own ability to manage their inflammatory status while at the same time sustaining anti-pathogen immunity. The studies highlighted in this manuscript outline the potential use of cell-based therapy for CF. The data demonstrate that 1) total bone marrow aspirates containing Cftr sufficient hematopoietic and mesenchymal stem cells (hMSCs) provide Cftr deficient mice >50% improvement in survival and improved management of infection and inflammation; 2) myeloid cells can provide sufficient Cftr to provide pre-clinical anti-inflammatory and antimicrobial benefit; 3) hMSCs provide significant improvement in survival and management of infection and inflammation in CF; 4) the combined interaction between macrophages and hMSCs can potentially enhance anti-inflammatory and antimicrobial support through manipulating PPARγ. These data support the development of optimized cell-based therapeutics to enhance CF patient’s own immune repertoire and capacity to maintain the balance between inflammation and pathogen management.

• bone marrow transplantation
• cystic fibrosis
• hematopoietic cells
• immune support
• infection
• inflammation
• macrophages
• mesenchymal stem cells

Chronic nontuberculous mycobacterial infections with Mycobacterium avium and Mycobacterium intracellulare complicate bronchiectasis, chronic obstructive airway disease, and the health of aging individuals. These insidious intracellular pathogens cause considerable morbidity and eventual mortality in individuals colonized with these bacteria. Current treatment regimens with antibiotic macrolides are both toxic and often inefficient at providing infection resolution. In this article, we demonstrate that human marrow‐derived mesenchymal stem cells are antimicrobial and anti‐inflammatory in vitro and in the context of an in vivo sustained infection of either M. avium and/or M. intracellulare.

• human mesenchymal stem cell donor potency and efficacy
• lung disease
• nontuberculous mycobacteria

• Humans
• Antiviral Agents/administration & dosage
• Controlled Clinical Trials as Topic/ethics
• Controlled Clinical Trials as Topic/standards
• COVID-19/mortality
• COVID-19 Drug Treatment
• Evidence-Based Medicine/ethics
• Evidence-Based Medicine/standards
• Placebos/administration & dosage
• Placebos/standards
• United States
• United States Food and Drug Administration/standards

• Animals
• Disease Models, Animal
• Female
• Glomerular Filtration Rate/physiology
• Kidney Transplantation/adverse effects
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/cytology
• Organ Preservation/methods
• Reperfusion Injury/therapy
• Swine

• Bone regeneration
• Exosomes
• Extra-cellular vesicles
• Mesenchymal stem cells
• Secretome
• Soluble factors

• Cartilage injury
• DMM surgery
• Ear-wound
• Ectopic calcification
• LG/J
• SM/J
• Synovitis

• adventitia
• cell therapy
• mesenchymal stem cell
• pericyte
• tissue engineering

Mesenchymal stem cells (MSCs) emerged as a promising therapy for tendon pathologies. Microfragmented adipose tissue (μFAT) represents a convenient autologous product for the application of MSC-based therapies in the clinical setting. In the present study, the ability of μFAT to counteract inflammatory processes induced by IL-1β on human tendon cells (TCs) was evaluated.

Cell viability and proliferation were evaluated after 48 hours of transwell coculture of TCs and autologous μFAT in the presence or absence of IL-1β. Gene expression of scleraxis, collagen type I and type III, metalloproteinases-1 and -3, and cyclooxygenase-2 was evaluated by real-time RT-PCR. The content of VEGF, IL-1Ra, TNFα, and IL-6 was evaluated by ELISA.

IL-1β-treated TCs showed augmented collagen type III, metalloproteases, and cyclooxygenase-2 expression. μFAT was able to reduce the expression of collagen type III and metalloproteases-1 in a significant manner, and at the same time, it enhanced the production of VEGF, IL-1Ra, and IL-6.

In this in vitro model of tendon cell inflammation, the paracrine action of μFAT, exerted by anti-inflammatory molecules and growth factors, was able to inhibit the expression of fibrosis and catabolic markers. Then, these results suggest that the application of μFAT may represent an effective conservative or adjuvant therapy for the treatment of tendon disorders.

• Mesenchymal stem cells
• Stem-cell research