Chronic obstructive pulmonary disease and asthma: mesenchymal stem cells and their extracellular vesicles as potential therapeutic tools

Abbaszadeh, Hossein; Ghorbani, Farzaneh; Abbaspour-Aghdam, Sanaz; Kamrani, Amin; Valizadeh, Hamed; Nadiri, Mehdi; Sadeghi, Armin; Shamsasenjan, Karim; Jadidi-Niaragh, Farhad; Roshangar, Leila; Ahmadi, Majid

doi:10.1186/s13287-022-02938-5

Stem Cell Research & Therapy

Table 1 Therapeutic application of various mesenchymal stem cells and their extracellular vesicles in preclinical COPD and asthma models

From: Chronic obstructive pulmonary disease and asthma: mesenchymal stem cells and their extracellular vesicles as potential therapeutic tools

Injury	Study type	type of MSCs	Infusion method	Dose of injection	Outcome	Reference
COPD	NCI-H292 airway epithelial cells	TNF-α and IL-1β-activated BM-MSCs	–	–	Increased airway epithelial wound healing via activation of the epidermal growth factor receptor	[48]
COPD	Mice model	BM-MSCs	Intravenous	4 × 10⁶ cells/mL	Relieved lung injury through promoting proliferation of endogenous lung stem cells	[49]
COPD	Rat model	BM-MSCs	Intratracheal	6 × 10⁶ cells/mL	Protect cigarette smoke-damaged lung and pulmonary function partly via VEGF–VEGF receptors	[50]
COPD	Mice model	BM-MSCs	Intravenous	4 × 10⁶ cells/mL	Ameliorate lung injury through anti-inflammatory and anti-bacterial effect	[51]
COPD	Rat model	BM-MSCs	Intratracheal	6 × 10⁶ cells/mL	Alleviated airway inflammation and emphysema through down-regulation of cyclooxygenase-2 via p38 and ERK MAPK pathways	[52]
COPD	Mice model	BM-MSCs	Intravenous	5 × 10⁵ cells/mouse	Exerted HGF dependent cytoprotective effects	[53]
COPD	Rat model	BM-MSCs	Intravenous	2 × 10⁶ cells/rat	Inhibited the progression of emphysema by differentiating into endotheliocytes and suppressing the apoptosis of endotheliocytes and oxidative stress	[54]
COPD	Mice model	HSP-VEGFA-BM-MSCs	Intravenous	–	Alleviated elastase-induced emphysema	[55]
Asthma	Mice model	BM-MSCs	Intravenous	10⁶ cells/mouse	Simvastatin and BM-MSCs combination therapy affects serum IgE as well as lung IL-13 and TGFβ levels more than BM-MSCs and simvastatin therapy alone	[63]
Asthma	Mice model	BM-MSCs	Intravenous	2.5 × 10⁵ cells	Controlled inflammation, immune-inflammatory factors and mitochondrial related genes, and prevent asthma immune-pathology	[64]
Asthma	Mice model	BM-MSCs	Bronchial	2.5 × 10⁵ cells		[64]
Asthma	Mice model	BM-MSCs	Intratracheal	10⁵ cells/mouse	Released different mediators and differentially affected airway and lung parenchyma	[65]
		AD-MSCs
		Lung-MSCs
Asthma	Rat model	BM-MSCs	Intratracheal	2 × 10⁶ cells/rat	CM and especially MSCs ameliorated pathological changes via intratracheal route presumably by targeting ICAM-1 and VCAM-1 in lung tissues	[66]
Asthma	Mice model	BM-MSCs	Intraperitoneal	10⁶ and 2 × 10⁶ cells	Ameliorated to the airway remodeling and airway inflammation both in the upper and lower airways via the inhibition of Th2 immune response in the murine model of AR	[67]
Asthma	Rat model	BM-MSCs	Intravenous	–	Affected on Th1/Th2 drift, and the Notch1/Jagged1 pathway and may participate in the homing of the BM-MSCs	[68]
Asthma	Mice model	BM-MSCs	Intravenous	2 × 10⁶ cells/mouse	Significantly reduced total cells and eosinophilia and serum OVA-specific IgE concentration and inhibited expressions of Th2 and Th17 cytokines and elevated levels of Treg cytokines	[69]
Asthma	Mice model	BM-MSCs	–	–	Alleviated asthma by inducing polarization of alveolar macrophages	[70]
Asthma	Mice model	BM-MSCs	retro-orbital	10⁶ cells/mouse	Participated in improved outcomes of remodeling by reversing excess collagen deposition and changing hyaluronan levels	[71]
COPD	Mice model	ASMCs-treated iPSC-MSCs	Intravenous	10⁶ cells/mouse	Alleviated oxidative stress-induced mitochondrial dysfunction in the airways	[72]
Asthma	Mice model	iPSC-MSCs mesenchymoangioblast-MSCs	Intranasal	10⁶ cells/mouse	Provided greater protection against experimental chronic allergic airways disease compared with a clinically used corticosteroid	[73]
COPD	Mice model	Pioglitazone pretreated WJ-MSCs	Intravenous	10⁴ cells/mouse	Produced greater lung regeneration, compared to non-augmented WJ-MSCs, in a mouse emphysema model	[74]
COPD	Mice model	WJ-MSCs	Intravenous	5 × 10⁴ cells/mouse	They didn’t confirm the effects of WJ-MSCs in COPD through this experiment	[75]
COPD	Mice model	HCB-MSCs	Intravenous	5 × 10⁴ cells/mouse	Improved the regenerative mechanisms based on the gene expression profile changes	[76]
Asthma	Mice model	HCB-MSCs	Intravenous	10⁵ cells/mouse	Suppressed severe asthma by directly regulating Th2 cells and type 2 innate lymphoid cells	[77]
Asthma	Mice model	AD-MSCs BM-MSCs	Intravenous	2.5 × 10⁷ cells/Kg	Suppressed AHR and airway inflammation and induced eosinophilic airway inflammation and lung histological changes	[81]
Asthma	Mice model	AD-MSCs	Intratracheal	10⁶ cells/mouse	Alleviated airway inflammation, improved airway remodeling, and relieved AHR	[17]
Asthma	Mice model	AD-MSCs	Intravenous	10⁵ cells/mouse	Reduced lung inflammation and remodeling while causing immunosuppression	[82]
Asthma	Feline model	AD-MSCs	Intravenous	2 × 10⁶, 4 × 10⁶, 4.7 × 10⁶ and 10⁷ cells/cat	Had a delayed potential in decreasing airway inflammation, AHR and remodeling	[83]
Asthma	Mice model	HAM-MSC-CM	Intravenous	10⁶ cells/mouse	Reduced inflammatory factors and fibrosis	[84]
Asthma	Rat model	HP-MSCs	Intraperitoneal	10⁶ cells/Kg	Suppressed airway inflammation in asthmatic rats by modulating Notch signaling	[85]
Asthma	In vitro	HP-MSCs	–	–	Reduced the IL-5 level experimentally in children with asthma	[86]
Asthma	Rat model	HP-MSCs	Intravenous	1 × 10⁷ cells/ml	Improved AHR and inflammation by modulating the Th17/Treg balance	[87]
Asthma	In vitro	DF-MSCs	–	–	Down-regulated Th2-mediated immune response in asthmatic patients mononuclear cells	[88]
COPD	Mice model	BM-MSCs and BM-MSC-Exos	Intraperitoneal	10⁶ cells	Combination treatment may act against early events caused by CS exposure owing to its anti-inflammatory and other mitochondrial transfer mechanisms	[89]
Asthma	In vitro	BM-MSC-Exos	–	–	Promoted immunosuppression of regulatory T cells	[90]
Asthma	Rat model	BM-MSCs and BM-MSC-Exos	Intravenous	5 × 10⁶ cells/cat	Reduced airway remodeling in lungs through the Wnt/β-catenin signaling pathway	[91]
Asthma	Mice model	BM-MSC-Exo-miR-188	–	–	Reduced bronchial smooth muscle cell proliferation in asthma through suppressing the JARID2/Wnt/β-catenin axis	[92]
Asthma	In vitro	BM-MSC-Exo-miR-146a-5p	–	–	Inhibited Th2 differentiation via regulating miR-146a-5p/SERPINB2 pathway	[93]
Asthma	Mice model	AD-MSC-EVs	Intranasal	10 μg	Alleviated AHR and allergic airway inflammation caused by the induction of Treg expansion	[94]
Asthma	Mice model	AD-MSC-Exo-miR-301a-3p	–	–	Regulated airway smooth muscle cells by targeting STAT3	[95]
Asthma	Mice model	AD-MSC-EVs	Jugular	37 μg	Acted differentially on lung mechanics and inflammation in experimental allergic asthma	[96]
Asthma	Mice model	mmu_circ_0001359-modified AD-MSC-Exos	Intravenous	200 μg	Attenuated airway remodeling by enhancing FoxO1signaling-mediated M2-like macrophage activation	[97]
Asthma	Mice model	iPSC-MSC- EV-miR-146a-5p	Intravenous	100 µg	Prevented group 2 innate lymphoid cell-dominant allergic airway inflammation	[98]
Asthma	Mice model	Hypoxic-hUC-MSC-EVs	Intravenous	40 μg	Attenuated allergic airway inflammation and airway remodeling	[99]
Asthma	RAW 264.7 cell line	HUC-MSC-Exos	–	–	Attenuated the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization	[100]
COPD	Mice model	P-MSC-Exo-MAPPS	–	–	Enhanced pulmonary function through decreasing serum concentrations of inflammatory cytokines, lung-infiltrated macrophages, neutrophils, and natural killer and antigen-presenting cells and elevated anti-inflammatory IL-10 and (Tregs)	[101]
Asthma	Mice model	hP-MSC-Exos	Intranasal	50 μg	Expanded lung IL-10-producing IMs, which may originate from spleen, thus contribute to protection against asthma	[102]

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