Secretome as a Tool to Treat Neurological Conditions: Are We Ready?
Abstract
:1. Introduction
2. Secretome Composition
2.1. Soluble Factors
2.2. Extracellular Vesicles
2.2.1. Exosomes
2.2.2. Microvesicles
2.2.3. miRNAs
3. Advantages of the Therapeutic Use of the Secretome Compared to MSCs
4. The Therapeutic Use of the Secretome in Neurological Diseases
4.1. Clinical Studies
4.2. Preclinical Studies
4.2.1. Alzheimer’s Disease
4.2.2. Multiple Sclerosis
4.2.3. Parkinson’s Disease
4.2.4. Stroke
4.2.5. Hypoxic-Ischemic Encephalopathy
4.2.6. Traumatic Brain Injury
4.2.7. Other Pathologies
5. Preconditioning
5.1. Three-Dimensional Culture and Three-Dimensional Scaffolds
5.2. Pharmacological or Chemical Compounds
5.3. Cytokines and Growth Factors
5.4. Hypoxia
5.5. Other Methods
6. Preparation of the Secretome
Secretome Formulation
7. Current Limitations
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
α-MEM | alpha minimal essential medium |
AD | Alzheimer’s disease |
ADSCs | adipose tissue |
BBB | Blood–brain barrier |
BDNF | brain-derived neurotrophic factor |
bFGF | basic fibroblast growth factor |
BME | Eagle’s basal medium |
BM | bone marrow |
CM | conditioned medium |
CNS | central nervous system |
DMEM | Dulbecco’s Modified Eagle’s Basal Medium |
EVs | extracellular vesicles |
Gal-1 | galectin-1 |
GDNF | glia-derived growth factor |
HIE | Hypoxic-ischemic Encephalopathy |
HGF-1 | hepatocyte growth factor 1 |
HSP | heat shock protein |
IFN-Y | interferon |
IGF-1 | insulin-like growth factor type 1 |
IL | interleukin |
IL-1Ra | interleukin 1 receptor antagonist |
miRNA | Micro-ribonucleic acid |
mRNA | Messenger ribonucleic acid |
MSCs | mesenchymal stem cells |
MVs | microvesicles |
NGF | nerve growth factor |
TBI | traumatic brain injury |
TGF-B | tumor growth factor B |
TNF-a | tumor necrosis factor α |
TSG101 | tumor susceptibility protein 101 |
VEGF | vascular endothelial growth factor |
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Source | Model | Priming | Outcomes | Ref. |
---|---|---|---|---|
hP-MSCs | Stroke | 3D culture/scaffolds | Functional recovery; ↓lesion volume; ↓cell death; ↑anti-inflammatory cytokines/neurotrophic factors; ↑neuronal differentiation; ↑angiogenesis; | [146] |
hUC-CM | SCI | 3D culture/scaffolds | Functional recovery; ↑angiogenesis; ↑remyelination | [137] |
hUC-CM | TBI | 3D culture/scaffolds | Functional recovery; ↓lesion volume; ↓cell death; ↓inflammation; ↓glial reactivity; ↑angiogenesis; ↑neurogenesis; ↑remyelination | [118] |
hBM-MSCs-Evs | AD | 3D culture/scaffolds | ↓Glial reactivity | [136] |
hBM-MSC-Ex | TBI | 3D culture/scaffolds | Functional recovery; ↓inflammation; ↑angiogenesis; ↑neurogenesis | [49] |
rBM-MSC | Stroke | Valproate and/or lithium chloride | Functional recovery; ↓lesion volume; ↑angiogenesis; ↑neurogenesis; ↑homing | [139] |
hADSCs | MS | Rapamycin | ↑Anti-inflammatory cytokines | [154] |
hWJ-MSC | HIE | Thrombin | Functional recovery; ↓lesion volume; ↓cell death; ↓glial reactivity | [151] |
hWJ-MSC | HIE | Thrombin | NA | [152] |
rBM-MSCs | HI | Tetramethylpyrazine | Functional recovery; ↑angiogenesis; ↑homing | [149] |
rBM-MSCs | Huntington | Valproate and/or lithium chloride | Functional recovery; ↓cell death | [147] |
rBM-MSCs | PD | Fasudil | Functional recovery; ↑neurotrophic factors; ↑angiogenesis; | [153] |
rBM-MSCs | Stroke | Hydrogen sulfide | Functional recovery; ↓lesion volume; ↓cell death; ↑neurotrophic factors | [148] |
rBM-MSCs | Stroke | Roxadustat (FG-4592) | Functional recovery; ↓cell death; ↓inflammation; ↓glial reactivity; | [155] |
rBM-MSCs | TBI | Calpain inhibitor (MDL28170) | Functional recovery; ↓lesion volume; ↓inflammation; ↓glial reactivity; ↑anti-inflammatory cytokines | [150] |
rBMSC-CM | HIE | Cobalt chloride | Functional recovery; ↓cell death | [138] |
rBMSC-CM | Neuroinflammation (induced by LPS) | Salidroside | ↓Cell death; ↓inflammation; ↓glial reactivity | [156] |
rBM-MSC | Stroke | IGF-1 | Functional recovery; ↑angiogenesis;↑neurogenesis | [140] |
rBM-MSCs | MS | SDF-1α | Functional recovery; ↓glial reactivity; ↑homing | [158] |
hASC-CM | PA | TNF-α and IFN-γ | Functional recovery; ↓cell death; ↓inflammation; ↓glial reactivity; ↓oxidative Stress; | [162] |
hASC-CM | TBI | TNF-α and IFN-γ | ↓Inflammation; ↓glial reactivity; ↓loss of visual acuity | [160] |
hASC-CM | TBI | TNF-α and IFN-γ | ↓Inflammation; ↓glial reactivity; ↓loss of visual acuity; | [165] |
hASC-CM | TBI | TNF-α and IFN-γ | ↓inflammation; ↓excitoxicity | [159] |
rASC-CM or hASC-CM | ICH | BDNF | ↓Lesion volume; ↓glial reactivity | [164] |
rBMSC-CM | Stroke | IL-1α | Functional recovery; ↓lesion volume; ↑body weight | [142] |
hBM-MSC-Evs | AD | TNF-α and IFN-γ | ↓Inflammation; ↓glial reactivity; ↑anti-inflammatory cytokines | [141] |
rBM-MSC-Ex | TBI | BDNF | Functional recovery; ↓cell death; ↑neurogenesis | [163] |
hADSCs | SCI | Hypoxia | ↓Cell death; ↑neurogenesis | [169] |
hOM-MSCs | ICH | Hypoxia | ↓Cell death; ↓inflammation; ↓glial reactivity | [168] |
rADMSCs | TBI | Hypoxia | Functional recovery; ↓cell death; ↓inflammation; ↑anti-inflammatory cytokines/neurotrophic factors; | [174] |
rBM-MSCs | Brain injury caused by cardiac arrest | Hypoxia | ↓Inflammation; ↑homing | [172] |
rBM-MSCs | ICH | Hypoxia | Functional recovery; ↓lesion volume; ↑neurotrophic Factors; ↑neurogenesis; | [170] |
rBM-MSCs | Stroke | Hypoxia | Functional recovery; ↓inflammation; ↑neurotrophic factors; ↑angiogenesis; ↑neurogenesis; ↑differentiation | [144] |
rBM-MSCs | Stroke | Hypoxia | Functional recovery; ↓lesion volume; ↓cell death; ↑homing | [173] |
rBM-MSCs | Stroke | Hypoxia | Functional recovery; ↑neurotrophic factors; ↑angiogenesis; ↑neurogenesis; | [171] |
hASC-CM | TBI | Hypoxia | Functional recovery; ↓inflammation; ↓glial reactivity; ↓cell death | [178] |
hBMSC-CM | TBI | Hypoxia | Functional recovery; ↓lesion volume; ↓cell death | [119] |
rBMSC-CM | Stroke | Hypoxia | Functional recovery; ↓cell death; ↑angiogenesis | [177] |
rBM-MSC-Ex | AD | Hypoxia | Functional recovery; ↓inflammation; ↓glial reactivity; ↑anti-inflammatory cytokines/neurotrophic factors | [143] |
hUC-MSCs-Ex | Stroke | Hypoxia | Functional recovery; ↑body weight | [180] |
hUC-MSCs-Ex | TBI | Hypoxia | Functional recovery; ↓cell death; ↓inflammation; ↑angiogenesis; ↑neurogenesis | [179] |
rBM-MSCs | SCI | Low-intensity pulsed ultrasound | Functional recovery; ↓lesion volume; ↓glial reactivity; ↑neurotrophic factors | [184] |
rBM-MSCs | Stroke | Ischemic brain tissue extract | ↓Lesion volume; ↓cell death; ↑anti-inflammatory cytokines/neurotrophic Factors; | [181] |
hUC-CM | TBI | Traumatically injured brain tissue extract | Functional recovery; ↓cell death; ↑neurotrophic factors; ↑neurogenesis; ↑homing; | [25] |
hUC-MSCs-Ex | Stroke | Cerebral infarct tissue extracts | Functional recovery; ↓lesion volume; ↓cell death; | [183] |
Source | Model | Priming | Medium | Density | Conditioning Time | Concentration | T Volume Administered | N° Administrations | Ref. |
---|---|---|---|---|---|---|---|---|---|
rBMSC | AD | No | Serum-free RPMI | 1 × 106 cells | 24 h | Ultrafiltration using centrifugal filters (unspecified) | 25 μL | 4 or 8 | [88] |
hBMSC | AD | No | Neurobasal-A | 2.4 × 104 cells/mL | 24 h | INA | 4 μL or 8 μL | 1 or 2 | [39] |
SHED, BMSC and FibroMSC | AD | No | Serum-free DMEM | 1 × 104 cells/cm2 | 48 h | INA | 400 μL | 8 | [89] |
hWJMSC (differentiate into Ols) | EAE | No | Serum-free DMEM/F12 | INA | 72 h | 100-fold with ultrafiltration using 3 kDa cut-off | 140 μL | 14 | [96] |
rASC | HIE | No | BME | 4 × 106 cells/cm2 | 24 h | 250-fold by 10,000 cut-off | 10 μL | 1 | [36] |
PSC-EMSC | HIE | No | Serum-free α-MEM | 9.2 × 104 cells/cm2 | 24 h | Removal of ions and molecules below 1kDa | 84 μL | 7 | [112] |
hDPSC/hBMSC | Hippocampal neurodegeneration | No | Serum-free basal | NA | 24 h | Not concentrated or diluted | 8 μL | 1 | [90] |
hBMSC | Impaired astrocytic exocytosis (transgenic model) | No | Neurobasal A | 4.0 × 103 cells/cm2 | 24 h | INA | 0.5 μL | 2 | [131] |
hUCMSC | NA | No | Serum-free DMEM | 1 × 104 cells/cm2 | 72 h | 10-fold by 3 kDa cut-off | 200 µL | 1 | [21] |
hUCPVC | NA | No | Neurobasal A | 4.0 × 103 cells/cm2 | 24 h | INA | 0.5 μL | 1 | [16] |
rBMSC | Neuropathic pain | No | Serum-free DMEM | 7 × 106 cells | 24 h | 15-fold using ultrafiltration units (unspecified) | 100 μL | 1 | [133] |
rBMSC | SCI | No | DMEM with low glucose and with/FBS | 5 × 103 cells/cm2 | 24 h | INA | 480 µL | 16 | [132] |
hASC | Stroke | No | Serum-free α-MEM | INA | 48 h | INA | 0.5 μL | 1 | [103] |
rBMSC | Stroke | No | DMEM/F12 supplemented with 2% LE rat serum | INA | 24 h | 10-fold by 5 kDa cut-off | INA | 1 | [102] |
hESCMSC | Stroke | No | DMEM containing 0.05% human serum albumin and 2 mM L-glutamine, without FBS | INA | 24 h | 100-fold with 3 kDa cut-off | 5 μL or 10 μL | 1 or 2 | [104] |
hSHEDMSC, hBMSC | Stroke | No | Serum-free DMEM | 4 × 105 cells/cm2 | 48 h | INA | 100 μL | 13 | [101] |
hUCMSC | Stroke | No | Serum-free DMEM/F12 | 1 × 104 cells/cm2 | 24 h | INA | 140 μL | 14 | [100] |
hBMSC | TBI | No | Serum-free DMEM | 2 × 106 cells/cm2 | 24 h | 25-fold by 3 kDa cut-off | ≈275 μL | INA | [37] |
hBMSC | TBI | No | Serum-free DMEM | 2 × 106 cells/cm2 | 24 h | 25-fold by 3 kDa cut-off | ≈1699 μL | 6 | [119] |
hUCMSC | TBI | No | Serum-free, low-glucose DMEM | 2 × 106cells | 24 h | 100 kDa cut-off (unspecified) | 3 μL | 1 | [25] |
hUCPVC | TBI | No | Serum-free EBM-2 | 2.5 × 103 cells/cm2 | 72 h | NA | 4 μL | 1 | [120] |
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da Silva, A.V.; Serrenho, I.; Araújo, B.; Carvalho, A.M.; Baltazar, G. Secretome as a Tool to Treat Neurological Conditions: Are We Ready? Int. J. Mol. Sci. 2023, 24, 16544. https://doi.org/10.3390/ijms242216544
da Silva AV, Serrenho I, Araújo B, Carvalho AM, Baltazar G. Secretome as a Tool to Treat Neurological Conditions: Are We Ready? International Journal of Molecular Sciences. 2023; 24(22):16544. https://doi.org/10.3390/ijms242216544
Chicago/Turabian Styleda Silva, Andreia Valente, Inês Serrenho, Beatriz Araújo, Alexandre Martins Carvalho, and Graça Baltazar. 2023. "Secretome as a Tool to Treat Neurological Conditions: Are We Ready?" International Journal of Molecular Sciences 24, no. 22: 16544. https://doi.org/10.3390/ijms242216544