Regulatory Role of Mesenchymal Stem Cells on Secondary Inflammation in Spinal Cord Injury

Figures & data

Figure 1 Schematic depicting the activation and migration of resident and peripheral immune cells following SCI. After primary injury, resident astrocytes, microglia, and other glial cells are immediately activated and migrate to the injury site (top). Subsequently, peripheral inflammatory cells including neutrophils, bone marrow-derived macrophages, and lymphocytes infiltrate into the epicenter of the injured spinal cord, and these activated immune cells can exacerbate damage, causing a wider range of secondary injury. Glial cells (mainly astrocytes) form glial scar to seclude the damaged area, and microglia are mainly present around the injury site (middle). These persistent pathophysiological changes ultimately result in severe dysfunction below the damaged segment (bottom).

Table 1 The Immunomodulatory Mechanisms of Transplanted MSCs in Improving the Prognosis of SCI

Species of MSCs	Source	Model	Dose (Number)	Injection Site	Infusion Time	Effect	Molecular Mechanism	Refs.
Mice	Adipose	Mice	1.0× 10^6	Intralesional	The day after SCI	Promote functional recovery	Inhibit the infiltration of macrophages and reduce the expression of TNF-α, IL-1β and IL-6	[109]
Human	Bone marrow	Rat	N/A	Intralesional	7 days after SCI	Promote functional recovery	Reduce TNF-α, IL-1β, IL-2, IL-6 and IL-12, increase the levels of MIP-1α	[110]
Human	Bone marrow	Mice	5.0×10^5	Intralesional	The day following SCI	Improve locomotor activity and suppress SCI-related damage	Up-regulate the levels of TSG-6, IL-10, TGF-β and IL-4, induce an AAM environment	[111]
Human	Bone marrow	Rat	1.0× 10^6	Intralesional	3 days after SCI	Promote functional recovery	Activate M2 macrophages, inhibit M1 macrophages, up-regulate the levels of IL-4 and IL-13, down-regulate the levels of TNF-a and IL-6	[112]
Rat	Bone marrow	Rat	1.0×10^6	Intravenous	24 hours after SCI	Promote functional recovery	Suppress the expression of pro-inflammatory cytokines such as TNF-α and IL-1β	[113]
Human	Umbilical cord	Mice	1.0× 10^6	Intralesional	14 days after SCI	Promote functional recovery	Promote the polarization of M2 macrophages, reduce the expression of IL-7, IFN-γ, and TNF-α, increase the expression levels of IL-4 and IL-13	[114]
Human	Umbilical cord	Mice	1.0×10^5	Intralesional	1 day after SCI	Improve locomotor performance	Shift the macrophage phenotype to the M2 phenotype	[115]
Human	Deciduous teeth	Rat	6.0×10^5	Intralesional	The day after SCI	Promote functional recovery	MCP-1 and ED-Siglec-9 secreted by MSCs synergistically induce M2 macrophages, suppress proinflammatory mediators such as IL-1 and TNF-a	[116]
Rat	Peripheral blood	Rat	2.0×10^4	Intralesional	30 minutes after SCI	Promote functional recovery	Inhibit Th17 cells, activate Treg cells, down-regulate the levels of IL-6 and IL-17a	[117]

Abbreviations: MIP-1α, macrophage inflammatory protein-1α; AAM, alternatively activated M2; N/A, not applicable.

Table 2 Completed Clinical Trials of MSCs in the Treatment of SCI

Clinical Trials. Gov Identifier	Status	Phase(s) (No. Enrolled)	Completion Date	Primary End Point	Ages (Years)	Intervention	Transplantation	Findings
NCT02482194	Completed	I (N=9)	Mar 2016	Safety	18~50	Autologous BM-MSCs	Intrathecal	Intrathecal injection of BMMSCs is safe with no serious adverse event
NCT01676441	Terminated	II/III (N=20)	Mar 2021	Safety, ASIA score	16~65	Autologous BM-MSCs	Intrathecal	Patients receiving BM-MSCs demonstrate improved in the muscle tension and in ADL, as well as significant MRI and electrophysiological changes
NCT02481440	Completed	I/II (N=102)	Mar 2020	Safety, ASIA score	18~65	Allogeneic hUC-MSCs	Intrathecal	Intrathecal injection of hUC-MSCs is safe with no serious adverse event
NCT02152657	Completed	N/A (N=5)	Dec 2016	Safety, MRI	18~65	Autologous MSCs	Percutaneous	N/A
NCT02981576	Completed	I/II (N=14)	Jan 2019	Safety and efficacy, ASIA score, MRI	18~70	Autologous BM-MSCs and AD-MSCs	Intrathecal	N/A
NCT02570932	Completed	II (N=10)	Dec 2017	IANR-SCIFRS	18~70	Autologous BM-MSCs	Intrathecal	Patients receiving BM-MSCs show variable clinical improvement in sensitivity, motor power, spasms, spasticity, neuropathic pain, sexual function or sphincter dysfunction without any adverse event
NCT01769872	Completed	I/II (N=15)	Jan 2016	Safety and effect, ASIA score	19~70	Autologous AD-MSCs	Intrathecal	N/A
NCT01274975	Completed	I (N=8)	Feb 2010	Safety	19~60	Autologous AD-MSCs	Intravenous	N/A
NCT01624779	Completed	I (N=15)	May 2014	MRI	19~70	Autologous AD-MSCs	Intrathecal	N/A
NCT04288934	Completed	I (N=20)	Sep 2020	ASIA score, ISNCSCI, SCIM III	18~70	Autologous BM-MSCs, WJ-MSCs	Intralesional.	N/A
NCT01873547	Completed	III (N=300)	Dec 2015	Safety, ASIA score	20~65	Allogeneic UC-MSCs	Intrathecal	N/A
NCT01909154	Completed	I (N=12)	Mar 2015	Safety	18~60	Autologous BM-MSCs	Intrathecal	Intrathecal administration of BM-MSCs is safe with no adverse events
NCT00816803	Completed	I/II (N=80)	Dec 2008	Safety, MRI	10~36	Autologous BM-MSCs	Intrathecal	Intrathecal injection of BM-MSC is safe with no long-term cell therapy-related side effects
NCT02165904	Completed	I (N=10)	May 2016	ASIA score	18~70	Autologous BM-MSCs	Intrathecal	Patients treated with BM-MSCs show improvements in sensitivity, motor function, sexual function and urinary control
NCT02510365	Unknown	I (N=20)	Dec 2021	Safety and efficacy	18~65	Allogeneic UC-MSCs	Intralesional	UC-MSCs transplantation is safe with no obvious adverse symptoms
NCT01393977	Unknown	II (N=60)	May 2012	EET	20~50	Allogeneic UC-MSCs	Intrathecal	Patients receiving UC-MSCs demonstrate improved self-care ability, muscular tension, maximum urinary flow rate as well as maximum bladder capacity
NCT01162915	Suspended	I (N=10)	May 2014	Safety	18~65	Autologous BM-MSCs.	Intrathecal	N/A
NCT01325103	Completed	N/A (N=14)	Dec 2012	Safety	18~50	Autologous BM-MSCs	Intralesional	Patients treated with BM-MSCs show improvement in both urinary and nervous system function and AISA score
NCT03003364	Completed	I/II (N=10)	Feb 2020	Safety	18~ 65	Allogeneic WJ-MSCs	Intrathecal	Intrathecal transplantation of WJ-MSCs is safe with no significant side effects
NCT01694927	Unknown	II (N=30)	Jun 2014	Safety	2~65	Autologous MSCs	Intrathecal	N/A
NCT02574572	Unknown	I (N=10)	Jun 2020	MRI	18~65	Autologous MSCs	Intralesional	N/A
NCT01446640	Unknown	I/II (N=20)	Jun 2014	Safety	16~60	Autologous BM-MSCs	Intrathecal	N/A
NCT02688049	Unknown	I/II (N=30)	Dec 2021	ASIA score, SSEP, MEP	18~65	Autologous BM-MSCs	Intralesional	N/A
NCT02352077	Unknown	I (N=30)	Dec 2021	Safety	18~65	Autologous BM-MSCs	Intralesional	N/A
NCT05018793	Suspended	I (N=15)	Dec 2025	Safety	Child, adult, older	Autologous AD-MSCs	Intrathecal	Intrathecal administration of AD-MSCs is safe with no adverse events
NCT04213131	Unknown	N/A (N=42)	Jan 2021	Neurologic function score, ASIA score	20~65	Allogeneic hUC-MSCs	Intravenous	N/A

Abbreviations: ASIA, American spinal injury association; ISNCSCI, international standards for neurological classification of SCI; MEP, motor evoked potentials; SSEP, somatosensory evoked potentials; MRI, magnetic resonance imaging; SCIM, spinal cord independence measure; IANR-SCIFRS, neurorestoratology-spinal cord injury functional rating scale; N/A, not applicable; EET, electromyogram and electroneurophysiologic test; hUC-MSCs, human umbilical cord-derived mesenchymal stem cells; UC-MSCs, umbilical cord derived mesenchymal stem cells; AD-MSCs, adipose tissue-derived mesenchymal stem cells; WJ-MSCs, wharton’s jelly mesenchymal stem cells.

Figure 2 MSCs improve SCI prognosis via immunomodulatory effects. These transplanted MSCs inhibit an excessive inflammatory response by up-regulating anti-inflammatory immune cells and associated cytokines and down-regulating the pro-inflammatory immune cells and associated cytokines, thereby promoting anatomical repair and functional recovery.

Notes: ↑, promotion; ↓, inhibition.

Figure 3 Preconditioning enhances the immunomodulatory ability and survival rate of MSCs in SCI. After SCI, the local harsh microenvironment causes a large amount of transplanted MSCs apoptosis. Various preconditioning strategies, including genetic modification, cytokines, hypoxia or other chemical molecules, can improve the immunomodulatory capacity, survival rate and homing ability of transplanted MSCs.

Note: ↑, promotion.

Table 3 The Immunosuppressive Effect of Pretreated MSCs and Extracellular Vesicles Secreted by MSCs in SCI

Source	Pretreatment	Dose (Number)	Model	Way	Infusion time	Secretion of MSCs	Immunomodulatory Mechanism	Effect	Refs.
Human umbilical cord	Hypoxia	1×10^5	Rat	Intralesional	N/A	N/A	Up-regulate the levels of regenerative neurotrophic factors, inhibit microglial/macrophage infiltration	Promote functional recovery	[184]
Human gingiva	Vesicular moringin nanostructures	1×10^6	Mice	Intravenous	1h hour after SCI	N/A	Increase the levels of anti‐inflammatory cytokines such as IL‐10 and TGF‐β	Promote functional recovery	[185]
Rat bone marrow	Hypoxia	1×10^6	Rat	Intralesional	The day following SCI	N/A	Down-regulate the levels of pro‐inflammatory cytokines such as TNF-α, IL-1β and IL-6	Improve motor and sensory function	[186]
Human umbilical cord	N/A	1, 2, 3ug	Rat	Intrathecal	24 h after SCI	EVs	Decrease the expression of caspase-1, IL-1, IL-18 and TNF-α	Improve locomotor function	[187]
Human umbilical cord	N/A	25μg	Mice	Intravenous	1 h and 7 days after SCI	N-NVs	N-NVs shift the balance from M1 to M2 macrophages	Promote functional recovery	[142]
Rat bone marrow	Hypoxia	200μg	Mice	Intravenous	The day following SCI	Exosome	Promote microglia/macrophage polarization from M1 to M2 phenotype, inhibit the TLR4 pathway	Promote functional recovery	[188]
Rat bone marrow	N/A	2.5×10^9	Rat	Intravenous	1 week after SCI	Exosome	Increase the production of anti-inflammatory cytokines, block M2 macrophages from converting to an M1 pro-inflammatory activation state	N/A	[189]
Rat bone marrow	N/A	N/A	Rat	Intravenous	7 consecutive days after SCI	Exosome	Increase the expression levels of anti-inflammatory factors such as IL-10 and IL-4, decrease the levels of TNF-a, IL-1b and MCP-1	Promote functional recovery	[190]
Human umbilical cord	Overexpression of NT-3	1×10^6	Rat	Intralesional	1 week after SCI	NT-3	Reduce the accumulation of immunoreactive macrophages/microglia	Promote functional recovery	[191,192]
Mice bone marrow	Overexpression of IGF-1	1×10^6	Mice	Intralesional	N/A	IGF-1	Up-regulate antioxidant defense genes and the expression levels of Mrc1, Nfe2L2, reduce the levels of MDA, nitrite	Promote functional recovery	[193]
Rat bone marrow	N/A	200μg	Rat	Intravenous	The day following SCI	Exosome	Suppress the activation of microglia and A1 astrocytes, decrease the levels of TNF-a, IL-1b and IL-6	Promote functional recovery	[194]
Rat bone marrow	N/A	40μg	Rat	Intravenous	30 minutes after SCI	Exosome	Reduce the proportion of A1 astrocytes and the levels of TNF-α, IL-1α and IL-1β	Promote functional recovery	[161]

Abbreviations: EVs, extracellular vehicles; N-NVs, normal MSC-derived nanovesicles; NT-3, neurotrophin-3; IGF-1, insulin-like growth factor 1; Mrc1, recombinant mannose receptor C type 1; Nfe2L2, recombinant nuclear factor erythroid 2 like protein 2; MDA, malondialdehyde; N/A, not applicable.

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