Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells and Their Contribution to Angiogenic Processes in Tissue Regeneration
Abstract
:1. Introduction
2. Mesenchymal Stem/Stromal Cells from Adipose Tissue (AT-MSCs)
2.1. Biology of AT-MSCs
2.2. Paracrine Activity and Secretome of AT-MSC
3. AT-MSC-Derived Extracellular Vesicles (EVs): Exosomes (Exo) and Microvesicles (MVs)
3.1. Mode of Formation
3.2. Biological Content
3.3. Intercellular Communication
3.4. AT-MSC-Derived Extracellular Vesicles (EVs)
4. Effect of AT-MSCs on Angiogenic Processes
5. AT-MSCs and Their Derivatives: Contribution to Regenerative Processes
5.1. Preclinical Studies on AT-MSCs in Tissue Regeneration
5.2. Clinical Application of AT-MSCs and Their Derivatives in Tissue Regeneration
6. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AMPs | antimicrobial peptides/proteins |
ANG | angiogenin |
ANGPTL4 | angiopoietin-related protein 4 |
Ang-1 | angiopoietin 1 |
ASCs | adipose tissue-derived stromal/stem cells |
AT-MSCs | adipose tissue-derived mesenchymal stem cells |
BDNF | brain-derived neurotrophic factor |
BM-MSCs | bone marrow derived mesenchymal stem cells |
CCL2 | C-C Motif chemokine ligand 2, MCP-1 |
CCL5 | C-C motif chemokine ligand 5, RANTES |
CCL7 | C-C Motif chemokine ligand 7 |
CDH5 | VE-cadherin (vascular endothelial cadherin) |
CM | conditioned medium |
c-Myc | transcription factor c-Myc |
CXCR4 | C-X-C chemokine receptor type 4 |
CXCR7 | C-X-C chemokine receptor type 7 |
DMD | Duchenne muscular dystrophy |
ENA-78 | epithelial neutrophil activating peptide |
EPCs | endothelial progenitor cells |
EVs | extracellular vesicles |
Exo | exosomes |
FGF | fibroblast growth factor |
GDNF | glial-derived neurotrophic factor |
GRO | growth-regulated protein |
HATMSC1 | human adipose tissue MSCs cell line |
hCAP18/LL37 | human cationic antimicrobial protein |
HGF | hepatocyte growth factor |
HIF1α | hypoxia-inducible factor 1-alpha |
HLA ABC | human leukocyte antigen, major histocompatibility complex, class I |
HLA DR | human leukocyte antigen, major histocompatibility complex, class II |
HO-1 | heme oxygenase-1 |
HUVEC | human umbilical vein endothelial cells |
ICAM-1 | intercellular adhesion molecule 1 |
IDO | indoleamine 2,3-dioxygenase |
IFN-γ | interferon gamma |
IGF | insulin-like growth factor |
IL | interleukin |
KDR | kinase insert domain receptor, FLK1, vascular endothelial growth factor receptor 2 |
LPS | lipopolysaccharides |
MCP-1 | monocyte chemoattractant protein-1, CCL2 |
miR | microRNA |
MSCs | mesenchymal stem cells |
MMPs | matrix metalloproteinases |
MVs | microvesicles |
NANOG | homeobox protein NANOG, transcriptional factor |
NOTCH | a transmembrane receptor in a signaling pathway |
Oct4 | octamer-binding transcription factor 4 |
PDGFA | platelet derived growth factor A |
PDGF-BB | platelet derived growth factor-BB |
PDGFRα | platelet-derived growth factor receptor A |
PW1 | Peg3, paternally expressed gene 3, a marker of adult stem cells |
RANTES | regulated on activation, normal T cell expressed and secreted protein, CCL5 |
SDF-1 | stromal cell-derived factor 1, C-X-C motif chemokine 12, CXCL12 |
Sox2 | (sex determining region Y)-box 2, transcription factor |
SVF | stromal vascular fraction |
TGF-β | transforming growth factor β |
TLR3 | toll-like receptor 3 |
TNFα | tumor necrosis factor alpha |
uPA | urokinase-type plasminogen activator |
uPAR | urokinase-type plasminogen activator receptor |
VEGF | vascular endothelial growth factor |
VEGFR | vascular endothelial growth factor receptor |
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Study Number/Status | Type of Disease | Type of Therapy | Patients | Results | Ref. |
---|---|---|---|---|---|
Not reported Completed | Nonhealing diabetic foot ulcers (>3 cm in diameter) | Local injections of autologous adipose-derived stromal vascular fraction (SVF) cells (EPCs and MSCs), phase 1 study; injection into the target foot of a total dose of 30 × 106 SVF cells | 63 patients with type 2 diabetes and underlying microangiopathy | Improved ulcer healing: closure response rates among evaluable patients between 86% and 93% at the 6- and 12-month endpoints; changes in the vascular bed beneath the ulcer and structural characteristics of the arteries supplying the foot | [94] |
KB/27/2015 Bioethics committee at the Regional Specialist Hospital, Research and Development Center in Wroclaw, Poland Completed | Chronic venous stasis ulcers | Subcutaneous administration to the tissues surrounding the ulcers and under the ulcer bed of autologous AT-MSCs (3.0 × 105 to 2.3 × 107 cells) | 11 patients (12 ulcers) | Improvement in clinical condition observed in 75% of ulcers; complete healing occurred in 25% of ulcers | [96] |
NCT04746599 Recruiting ClinicalTrials.gov | Critical limb ischemia | Autologous fat grafting | 20 participants | No results posted | |
NCT04661644 Recruiting ClinicalTrials.gov | Critical limb ischemia | Clusters of adipose-derived mesenchymal stem cells (dose: 1 × 107 cells/1 mL/vial, phase 1; and 1 × 108 cells/1 mL/vial, phase 2), phase 1/2a clinical trial | 20 participants | No results posted | |
NCT04466007 Recruiting ClinicalTrials.gov | Critical ischemia of the lower limbs in diabetic patients without the possibility of revascularization | Allogeneic mesenchymal stromal cells derived from adipose tissue administered intramuscularly (low and high doses) | 90 participants | No results posted | |
NCT03968198 Recruiting ClinicalTrials.gov | Critical limb ischemia and peripheral artery disease | Autologous intramuscular administration of adipose tissue-derived mesenchymal stromal/stem cells (ASCs), phase 2 study | 43 participants | No results posted | |
NCT01824069 Completed ClinicalTrials.gov | Nonrevascularizable critical ischemia of the lower limbs | Intramuscular injection of autologous adult mesenchymal stem cells derived from adipose tissue (1 × 106/kg), phase 1 and 2a study | 10 participants | 7 patients were followed-up after the treatment for 1 year (phase 1b study). A statistically significant improvement in health-related quality of life in the post-treatment period was observed. An ankle-brachial index and clinical behavior of the limb improved during the follow-up. | [97] |
NCT01745744 Completed ClinicalTrials.gov | Critical chronic ischemic syndrome of the lower limb in nondiabetic patients | Infusion of mesenchymal stem cells derived from adipose tissue administered intraarterially: 0.5 × 106 cells/kg of patient weight and 1 × 106 cells/kg of patient weight, phase 2 study | 33 participants | No results posted | |
NCT01663376 Completed | Critical Limb Ischemia | Intramuscular injection of autologous adipose derived mesenchymal stem cells. Dose: 1 × 108–3 × 108 cells | 20 participants | Autologous AT-MSC implantation effectively increases blood flow. Above 66% of patients with non-healing ulcers experienced ulcer healing, only in the cases with an initially necrotic foot, no observable tissue regeneration occurred. There was clinical improvement in 100% of patients with a diabetic foot (3 patients) and in 58.3% of patients with Buerger’s Disease (7 patients) | [98] |
NCT01302015 Completed ClinicalTrials.gov | Buerger’s disease (thromboangiitis obliterans) | RNL-Vascostem (autologous adipose tissue-derived mesenchymal stem cells) dosage: intramuscular infusion, 5 × 106 cells/kg | 15 participants | ||
NCT04569409 Recruiting ClinicalTrials.gov | Diabetic foot ulcer | Application of a hydrogel sheet (ALLO-ASC-DFU) containing allogenic adipose-derived mesenchymal stem cells to diabetic grade 2 foot ulcer, phase 3 study | 104 patients | No results available yet | |
NCT04497805 Recruiting ClinicalTrials.gov | Diabetic foot ulcer | Application of a hydrogel sheet (ALLO-ASC-DFU) containing allogenic mesenchymal stem cells to diabetic grade 2 foot ulcer, phase 2 study | 64 participants | No results available yet | |
NCT04457037 Completed ClinicalTrials.gov | Trophic ulcer | Patients with trophic ulcers received standard treatment and autologous adipose-derived mesenchymal stem cells | 18 participants | No results available yet | |
NCT03276312 Completed ClinicalTrials.gov | Minor amputations of diabetic foot | Lipogems–local injection of autologous micro-fragmented adipose tissue | 112 participants | After 6 months, 80% of the micro-fragmented adipose tissue-treated feet healed and 20% failed compared to the control group. A significant improvement in terms of physical health-related quality of life and a significant reduction of the hospital length of stay was reported. | [99,100] |
NCT03183648 Active, not recruiting ClinicalTrials.gov | Burn | Application of a hydrogel sheet (ALLO-ASC-DFU) containing allogenic adipose-derived mesenchymal stem cells | 30 participants | No results available yet | |
NCT04280003 Recruiting ClinicalTrials.gov | Ischemic stroke | Intravenous treatment with allogenic adipose tissue-derived stem cells in a single dose of one million cells per kg, phase 2 study | 30 participants | No results available yet | [101] |
NCT02387723 Completed ClinicalTrials.gov | Heart failure | Patients with heart failure treated with culture-expanded adipose tissue-derived mesenchymal stem cells from healthy donors. The cells were injected directly into the myocardium | 10 participants | Four out of ten patients developed donor-specific de novo HLA class I antibodies, and two other patients had donor-specific antibodies at baseline. None of the patients had any clinical symptoms or changes in biochemical or inflammatory parameters. The cardiac function tended to improve after AD MSC treatment at 6-month follow-up. | [102] |
NCT01678534 Completed ClinicalTrials.gov | Ischemic Stroke | Intravenous treatment with allogeneic stem cells from adipose tissue, phase 2 study | 19 participants | No results posted | [103] |
NCT01449032 Completed ClinicalTrials.gov | Chronic ischemic heart disease (coronary artery disease, CAD) | Intramyocardial injections of autologous VEGF-A165-stimulated adipose-derived stem cells (ASCs), phase 2 study | 60 participants | Intramyocardially delivered ASC treatment was safe but did not improve exercise capacity compared to placebo in a pilot study. After a 3-year follow-up, patients receiving ASCs had improved cardiac symptoms and unchanged exercise capacity, in contrast to deterioration in the placebo group | [104,105] |
NCT04388761 Recruiting ClinicalTrials.gov | Ischemia reperfusion injury in patients with a kidney allograft | AMSC treatment via direct injection into the kidney parenchyma and intra-arterial infusion, phase 2 study | 15 participants | No results posted | |
NCT01257776 Completed ClinicalTrials.gov | Critical limb ischemia (CLI) in diabetic patients | Intra-arterial administration of autologous adipose-derived mesenchymal stem cells, phase 1 study | 33 participants | No results posted | |
NCT03865394 Completed ClinicalTrials.gov | Chronic wounds in diabetic foot syndrome | Application of allogeneic adipose-derived mesenchymal stem cells in fibrin gel | 46 participants | No results posted | |
NCT03183726 Completed ClinicalTrials.gov | Diabetic foot ulcer | Application of ALLO-ASC-DFU (a hydrogel sheet containing allogenic adipose-derived mesenchymal stem cells), phase 1 study | 4 participants | No results posted | |
NCT03754465 Recruiting ClinicalTrials.gov | Diabetic foot ulcer | Application of an ALLO-ASC-DFU sheet to diabetic foot ulcer (a hydrogel sheet containing allogenic adipose-derived mesenchymal stem cells), phase 2 study | 44 participants | No results posted | |
NCT03370874 Active, not recruiting ClinicalTrials.gov | Diabetic foot ulcer | Application of an ALLO-ASC-DFU sheet to diabetic foot ulcer (a hydrogel sheet containing allogenic adipose-derived mesenchymal stem cells), phase 3 study | 164 participants | No results posted | |
NCT02394873 Completed ClinicalTrials.gov | Deep second-degree burn wound | Application of an ALLO-ASC-DFU sheet (a hydrogel sheet containing allogenic adipose-derived mesenchymal stem cells), phase 1 study | 5 participants | No results posted | |
NCT05165459 Recruiting ClinicalTrials.gov | Venous keg ulcer | Venous leg ulcer treatment with adipose SVF (autologous adipose stromal vascular fraction) administered locally into the target ulcer. | 10 participants | No results posted | |
NCT04569409 Recruiting ClinicalTrials.gov | Diabetic Wagner grade 2 foot ulcers | Application of an ALLO-ASC-DFU sheet (a hydrogel sheet containing allogenic adipose-derived mesenchymal stem cells), phase 3 study | 104 participants | No results posted |
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Krawczenko, A.; Klimczak, A. Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells and Their Contribution to Angiogenic Processes in Tissue Regeneration. Int. J. Mol. Sci. 2022, 23, 2425. https://doi.org/10.3390/ijms23052425
Krawczenko A, Klimczak A. Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells and Their Contribution to Angiogenic Processes in Tissue Regeneration. International Journal of Molecular Sciences. 2022; 23(5):2425. https://doi.org/10.3390/ijms23052425
Chicago/Turabian StyleKrawczenko, Agnieszka, and Aleksandra Klimczak. 2022. "Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells and Their Contribution to Angiogenic Processes in Tissue Regeneration" International Journal of Molecular Sciences 23, no. 5: 2425. https://doi.org/10.3390/ijms23052425