Harnessing stem cell-derived exosomes: a promising cell-free approach for spinal cord injury

Lin, Miaoman; Alimerzaloo, Farzaneh; Wang, Xingjin; Alhalabi, Obada; Krieg, Sandro M.; Skutella, Thomas; Younsi, Alexander

doi:10.1186/s13287-025-04296-4

Stem Cell Research & Therapy

Table 1 Research on the treatment of SCI with exosomes derived from stem cells

From: Harnessing stem cell-derived exosomes: a promising cell-free approach for spinal cord injury

Year	Source of exosomes	SCI models	Administration route	Dose	Target(s)	Function(s)	References
2022	NSC	C57BL/6 mouse T10 contusion SCI	Tail vein	Unspecified (in 30 ul PBS for once)	miR-374-5p/STK-4 axis	Promote autophagy	[32]
2019	NSC	SD rat T10 contusion SCI	Tail vein	200 μg in 200 μL of PBS for once	LC3B & beclin-1	Promote autophagy	[33]
2024	NSC	C57BL/6 mouse T10 contusion SCI	/ (Single-cell RNA sequencing)	Unspecified	TSC2/EGF & MDK Slc16a3/VEGF & MIF	Increase autophagic flux	[34]
2019	NSC	SD rat T10 contusion SCI	Tail vein	100 μg in 0.5 mL of PBS for once	miR-219a-2-3p-YY1/NF-κB	Suppress neuroinflammation and apoptosis, enhance pro-neuroregenerative capacities	[35]
2020	NSC	C57BL/6 mouse T10 contusive SCI	Tail vein	200 µg in 100 µL PBS at 30 min after SCI tills on 3, 6, 9, and 12 d post-SCI, respectively	VEGF-A	Promote microvascular regeneration, tissue healing, and reduce tissue cavity formation	[36]
2024	hAMSC	SD rat T10 contusion SCI	Tail vein	200 μg in 200 µl PBS for once	reduce ROS and inflammatory cytokines levels, including TNF-a, IL-6, and IL-1β	Promote the functional recovery of TSCI rats by Reduce neuroinflammation, cell apoptosis, astrogliosis, and lesion volume, protect the BSCB, and enhance angiogenesis and axonal regeneration	[55]
2024	ADSC	Hemin induced mouse microglia BV2 post-SCI inflammation cell model	Bioinformatics prediction	Unspecified (with a concentration of 3 × 10⁹ particles/ml for co-culture)	LRRC75A-AS1/FDFT1	Inhibit inflammation	[17]
2024	BMSC	Rat T10 contusion SCI	Tail vein	100 μg in 0.5 mL PBS for 7 consecutive days	inhibit pro-inflammatory factors (TNF-α, IL-1β, and IL-6)	Modulate neuronal apoptosis and inflammation	[57]
2024	BMSC	SD rat T10 contusion SCI	Tail vein	Unspecified (in 500ul PBS for once)	miR-146a-IRAK1\TRAF6\NF-κB p65	Reduce inflammatory factors and oxidative stress	[43]
2024	Hypoxia-preconditioned ADSC	C57BL/6 mouse T10 contusive SCI	Tail vein	200ug in 200ul PBS for once	circ-Wdfy3/miR-423-3p/GPX4	Reduce the levels of ROS and inflammatory cytokines	[50]
2024	AMSC	SD rat T6/7 contusion SCI	Tail vein	100 μg in 1 mL of PBS for 3 consecutive days	miR-125a-3p	Diminish inflammatory Neutrophil extracellular trap formation	[54]
2024	UCMSC	Rat T10 contusion SCI	Tail vein	100 ug in 0.5 mL PBS for once	NF-κB/MAPK	Reduce the inflammatory response	[49]
2023	hPMSC	SD rat T9 contusion SCI	Tail vein	200 ug in 200ul PBS for once	unspecified	Ameliorate histological changes, reduce inflammation, apoptosis, and gliosis, modulate oxidative stress (in combination with Hyperbaric Oxygen)	[87]
2023	BMSC	SD rat contusion SCI	Tail vein	200 μg in 500 μL PBS for once	miR-216a-5p-TLR4/NF-κB	Attenuate neuronal injury and microglia-mediated inflammation	[45]
2021	BMSC	SD rat T9/10 contusion SCI	Tail vein	200 μg in 0.5 mL PBS for once	miR-145-5p-TLR4/NF-κB	Reduce inflammation	[46]
2021	BMSC	SD rat T10 contusion SCI	Tail vein	Unspecified (200 µL of exosomes for 7 consecutive days)	TLR4/MyD88/NF-κB	Reduce apoptosis and inflammatory response	[47]
2023	hUCMSC	SD rat T10 contusion SCI	Injected into the surface of the spinal cord	unspecified	miR-138-5p-NLRP3-caspase1 & Nrf2-keap1	Reduce the inflammatory response	[48]
2023	hUCMSC	SD rat spinal cord ischemia/reperfusion model	Intrathecally injection	20 μg exosomes in 10 μL PBS for once	miR-146a-5p-TLR4/NF-κB	Alleviate spinal cord injury and inflammatory cytokines	[44]
2023	BMSC	SD rat T10 contusion SCI	Tail vein	200 μg in 500 μl PBS for once	miR-137	Enhance neuron viability while reducing tissue injury and diminish tissue inflammation	[59]
2023	BMSC	SD rat T10 contusion SCI	Tail vein	200 μg in 500 μl PBS at 1h, 7, 14 d after SCI	miR-146a	Promote neuron viability while repressing apoptosis and inflammation	[58]
2023	BMSC	SD rat T10 contusion SCI	Tail vein	100 μg in 0.5 mL of PBS (equivalent to 1 × 10¹⁰ particles) for consecutive 5 days	netrin-1- Unc5b/PI3K/AKT/mTOR	Mitigate the inflammatory response, reduce pyroptosis, and promote the growth of axons	[90]
2022	hUCMSC	C57BL/6J T11&12 contusion SCI	Caudal vein	50 μg in 200 μL of PBS for once	TNF-α/NF-κB	Attenuate the inflammation and tissue damage	[91]
2022	BMSC	SD rat T10 contusion SCI	Tail vein	100 μg in 0.5 mL PBS for consecutive 7 days	miR-9-5p-HDAC5/FGF2	Inhibit LPS-induced apoptosis, inflammation, and ER stress in vitro. improve locomotor ability and alleviate histopathological damage and neuronal apoptosis in vivo	[51]
2019	hUCMSC	F344-rat T8 contusion SCI	Tail vein	100 μL of Ringer-lactate containing the hUCMSC-EVs secreted by 10⁶ hUCMSCs twice	quench the expression of pro-inflammatory cytokines (IL-1β and IL-6)	Anti-inflammatory and anti-scarring activities	[56]
2024	BMSC	C57BL/6J mouseT8 contusive SCI	Intrathecal injection	100 μg in 5 μL PBS for once	miR-21a-5p/PELI1	Enhance autophagy and suppression of pyroptosis in macrophage/microglia, and attenuate the inflammatory response	[53]
2020	hypoxia-preconditioned BMSC	C57BL/6 mouse T10 contusive SCI	Tail vein	200 μg in 200 μL PBS for once	miR-216a-5p-TLR4/NF-κB & PI3K/AKT	Shift microglia from the M1 phenotype to the M2 phenotype	[52]
2020	placental mesenchymal stem cell	mouse T10 contusive SCI	The epicenter of the SCI	Unspecified (with a concentration of 200 μg/μL) for once	unspecified	Promote endothelial cells formatted capillary-like structures in vitro and stimulate neoangiogenesis in vivo	[61]
2022	Hypoxia-pretreated hUCMSC	transection SCI	Transplanted to the spinal lesion	100 μg in 20 μL PBS (Encapsulation of exosomes in the hydrogel)	HIF-1α	Enhance angiogenesis and nerve regeneration	[62]
2020	BMSC	SD rat T10 contusion SCI	Tail vein	100 μg in 0.5 mL of PBS for once	miR-126-SPRED1 & PIK3R2	Promote angiogenesis and neurogenesis and attenuate apoptosis	[63]
2024	ADSC	SD rat T10 contusion SCI	Tail vein	100 µg in 1 ml PBS with DMSO for once	NRF2/SLC7A11/GPX4	Protect endothelial cells and promote their regeneration by inhibiting ferroptosis	[64]
2019	BMSC	SD rat T10 contusion SCI	Tail vein	200 μL of EV (200 μg/mL) for twice	NF-κB p65	Inhibit pericyte migration and improve the integrity Improvement of the BSCB	[65]
2021	hBMSC	SD rat T9 contusion SCI	Subcutaneous injection	100 μg in 100 μl of PBS, once a day for 1 week	TIMP2/MMP	Attenuate BSCB disruption	[66]
2023	UCMSC	Mouse T 10 Contusive SCI	Intranasally administered	1 mg/kg at 3 h and 3 and 6 days after SCI	RGD-CD146CD271-miR-501-5p/MLCK	Reduce the disruption of tight junctions, stabilize the BSCB	[19]
2022	BMSC	SD rat T10 contusion SCI	Unspecified	200 μg in 200 μl of PBS for once	Wnt/β-catenin	Reduce cell apoptosis and potentially reduce the activation of astrocytes and microglia cells	[92]
2019	BMSC	Wistar rat T10 hemisection SCI	Tail vein	100 μg in 0.5 mL of PBS for once	microRNA-21-5p/FasL	Attenuate apoptosis and improve neurological function	[93]
2019	hMSC	SD rat T9/10 contusion SCI	Intravenous injection	Unspecified	miR-21 and miR-19b -PTEN	Regulate the apoptosis and differentiation of neuron cells	[94]
2019	MSC	SD rat T9/10 contusive SCI	i.v. injection	Unspecified	MiR-21-PTEN/PDCD4	Inhibit the cell apoptosis of neurons	[95]
2022	hypoxia-induced ADSC	SD rat SCI	Tail vein	Unspecified	miR-499-5p-JNK3/c-Jun/MAPK10	Inhibit neuronal apoptosis	[96]
2021	hPMSC	SD rat T11 contusive SCI	Tail vein	50 μg in 100 μl PBS for twice	MEK/ERK/CREB	Modulate endogenous NPCs and enhance neurogenesis	[68]
2021	UCMSC	SD rat T10 contusive SCI	i.v. injection	200 μg for twice	miR-199a-3p/145-5p-NGF/TrkA	Promote neuronal differentiation and neurite outgrowth	[69]
2022	BMSC	Wistar rat T10 contusive SCI	Intrathecal injection	polyethylene catheter continuous injection of 25 μl BMSC-EV-injection, 50 nmol let-7a-5p for 3 days	let-7a-5p-HMGA2/SMAD2	Mediate the differentiation of NSCs and promotes the regeneration of neurons and their neurite outgrowth in glial scars	[70]
2022	iPSC	C57BL/6 mouse T11/12 contusive SCI	Tail vein	unspecified (200 μl for 3 days)	miR-199b-5p-Hgf /PI3K	Shift the polarization from M1 macrophage to M2 phenotype and regulate related inflammatory factors expression	[71]
2024	iPSC	C57BL/6 mouse T8 contusive SCI	Intrathecal injection	unspecified (with a concentration of 20 µg/µL) for once	let-7b-5p-LRIG3/PI3K/Akt	Modulate microglial/macrophage pyroptosis, promote axonal growth	[73]
2024	iPSC	C57BL/6 mouse T11/12 contusive SCI	i.v. injection	30 µg for once	miR-23b, miR-21-5p & miR-199b-5p	Reduce inflammatory cell infiltration and apoptosis	[72]
2022	DPSC	C57BL/6 mouse T11/12 contusive SCI	Tail vein	200 μg in 100 μl PBS for once	ROS-MAPK-NFκB P65	Reduce macrophage M1 polarization, attenuate the inflammatory response, and reduce neurological impairment	[26]

NSC = neural stem cells; SCI = spinal cord injury; PBS = phosphate buffered saline; miRNA, miR = microRNAs; Tsc2 = tuberous sclerosis 2; MDK = midkine; Slc16a3 = solute carrier family 16 member 3; VEGF = vascular endothelial growth factor; MIF = macrophage migration inhibitory factor; NF-κB = transcription factor kappa B; hAMSC = human amniotic mesenchymal stem cells; ROS = free radicals and reactive oxygen species; TNF-α = tumor necrosis factor-α; IL = Interleukin; ADSC = adipose-derived mesenchymal stem cells; BMSC = bone marrow mesenchymal stem cells; IRAK1 = interleukin-1 receptor-associated kinase 1; GPX4 = glutathione peroxidase 4; MAPK = mitogen-activated protein kinase; UCMSC = umbilical cord mesenchymal stem cells; hPMSC = human placental mesenchymal stem cells; TLR4 = toll-like receptor 4; MyD88 = myeloid differentiation factor 88; PI3K = phosphatidylinositol-3-kinase; PKB or AKT = protein kinase B; mTOR = mammalian target of the rapamycin; HDAC5 = histone deacetylase 5; FGF2 = fibroblast growth factor 2; LPS = Lipopolysaccharide; HIF-1α = hypoxia-inducible factor 1-alpha; SPRED1 = Sprouty-related EVH1 domain-containing protein 1; NRF2 = nuclear factor erythroid-2-related factor 2; SLC7A11 = solute carrier family 7 member 11; BSCB = blood-spinal cord barrier; TIMP2 = tissue inhibitors of matrix metalloproteinase 2; MMP = matrix metalloproteinase; RGD = Arg-Gly-Asp; MLCK = myosin light chain kinase; FasL = fas ligand; PTEN = phosphatase and tensin homolog; PDCD4 = programmed cell death 4 protein; MEK = mitogen-activated protein kinase kinase; ERK = extracellular signal-regulated kinases; CREB = cAMP response element binding; NGF = Neuronal growth factor; TrkA = Tropomyosin receptor kinase A; EV = extracellular vesicles; HMGA2 = high-mobility group A 2; iPSC = induced pluripotent stem cells; Hgf = hepatocyte growth factor; DPSC = dental pulp stem cell

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ISSN: 1757-6512

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