Some of the earliest preclinical studies to demonstrate the efficacy of MSCs in treating neurodegenerative disease were performed in Niemann-Pick type C mice (Bae et al., 2005; Bae et al., 2007) with the first AD-specific preclinical study being conducted in the late 2000’s. A study by Lee et al. demonstrated that intracerebral transplantation BM-MSCs into the dentate gyrus reduced Aβ levels and recruited microglia with an autophagy-prone morphology (Lee et al., 2009). In addition to the general MSC mechanisms of action described in previous sections, several studies have shown that human WJ- MSCs and hUC-MSCs not only reduce Aβ load and tau phosphorylation, but also improve memory and cognition in rodent models of AD (Xie et al., 2016; Lim et al., 2020; Park et al., 2021), demonstrating that the changes MSCs make to the biochemical environment of the brain translate to measurable cognitive benefit.

MSC exosomes alone have also been trialed in preclinical models of AD to great effect. Administration of the MSC extracellular vesicles alone mimicked the effects of administration of whole MSCs in mouse models of AD, reducing Aβ plaque levels and markers of microglial and astrocyte activation (Cone et al., 2021; Santamaria et al., 2021). Furthermore, MSC exosomes were shown to transiently increase memory in mice 7 days post administration as measured by the novel object recognition test. However, memory declined again by 14 days post-treatment (Santamaria et al., 2021).

The use of iron oxide nanoparticles (IONP) has also been explored as a method improved targeting of MSCs in murine models of AD. Application of an external magnetic field to the brains of AD mice guided human WJ-MSCs loaded with magnetic dextran-coated IONPs to the hippocampus (Hour et al., 2020). This approach could be further improved when combined with agents or techniques that temporarily disrupt the BBB to enhance MSC entry into the brain (Joshi et al., 2011; Wang et al., 2022). To our knowledge, the use of MSCs augmented with nanoparticles and magnetic fields in conjunction with MSCs has yet to be studied in humans.

Promising pre-clinical results have led to the initiation of many clinical trials investigating the safety and efficacy of MSCs in the treatment of AD; however, most have failed. One reason for this may be because rodent models of AD rely on a familial AD paradigm caused by mutations in APP, PSEN1, and PSEN2 (Ballard et al., 2011; Götz et al., 2018; Hernández and García, 2021), whereas in reality, about 95% of AD cases in humans are sporadic (Ballard et al., 2011; Götz et al., 2018). As a result, most preclinical trials, which rely on familial AD models, may be limited in their generalizability for human trials (Drummond and Wisniewski, 2017).

Overall, the published results from completed phase 1 and 2 clinical trials suggest that MSCs are safe and well-tolerated in patients with AD. One of the earliest phase 1 trials to be completed (NCT01297218) found that stereotactic injection of hUCB-MSCs was safe, with no treatment-related adverse events other than pain, headache, and dizziness related to the surgical implantation procedure itself (Kim H. J. et al., 2015). Stereotactic injection is an invasive route of administration and has since been used sparingly in AD trials. While some other trials have attempted to use intraventricular injection (Kim H. J. et al., 2021), most have opted to use intravenous or intranasal routes of administration.

In 2021, Kim et al. published results from another clinical trial (NCT02054208); this time a phase 1/2 double-blind study utilizing the same hUCB-MSCs but at higher doses and with 3 repeat administrations. Consistent with the 2015 study, this trial reported similar safety outcomes. Notably, it also found that MSC injection transiently reduced brain levels of Aβ and tau, although these effects dissipated by 4 weeks (Kim H. J. et al., 2021). A 36-month follow-up study of the same cohort has since been completed (NCT03172117), but to our knowledge the results have not yet been published.

Other clinical trials have investigated MSCs derived from different sources, including adipose tissue. A phase 1/2 study (NCT03117738) tested autologous AD-MSCs in patients with mild-to-moderate AD. MSCs were administered intravenously, and though several serious adverse events were recorded (i.e., diarrhea, acute pulmonary edema, and stage IV esophageal squamous cell carcinoma), the treatment was overall well-tolerated; however, the trial failed to show improvement in measures of cognition, including the ADAS-Cog and the MMSE. A follow-up phase 2b clinical trial of AstroStem cells (NCT04482413) was initiated in 2023 using a similar repeat-dose protocol in a larger study sample, but the trial has passed its estimated completion date.

A phase 1 trial using allogenic BM-MSCs intravenously reported no serious adverse events and noted increases in VEGF and IL-4 levels in treated groups. The IL-4 increase is noteworthy, as IL-4 may regulate apoptosis, microglial activation, and BDNF secretion (Brody et al., 2023). Similarly, a recently published phase 1/2 trial (NCT04388981) investigating allogenic AD-MSC-derived exosomes demonstrated excellent safety and modest cognitive improvement in the medium-dose arm (Xie et al., 2023).

Several upcoming trials are pursuing novel strategies. A phase 1 basket-design study (NCT06607900) is evaluating human umbilical cord MSC-derived exosomes for multiple neurodegenerative diseases, including AD, with completion expected by 2027. A phase 1/2 trial (NCT06775964) in the recruiting phase aims to target the late-presymptomatic/prodromal stage of AD using autologous AD-MSCs. Targeting the early stages of AD may elicit therapeutic benefit before the cascade of neuroinflammation and neurodegeneration becomes irreversible. Another trial will focus specifically on AD patients with behavioral symptoms who are receiving antipsychotic medications, thus taking a novel approach of addressing the neuropsychiatric symptoms that are prevalent and burdensome yet often overlooked (Zhao et al., 2016). Additionally, results are awaited from a phase 1/2 study using human placenta-derived MSCs in probable AD patients over age 50 (NCT02899091).

In summary, current phase 1 and phase 2 clinical trials investigating MSCs and their exosomes for the treatment of AD have shown an excellent safety profile overall, but more extensive phase 2 and 3 studies are required to further characterize their ability to modify the course of AD. A brief summary of clinical trials involving MSCs for AD is presented in Table 1.

Animal models of PD have historically been created through use of toxic molecules like 6-hydroxydopamine (6-OHDA), MPTP, MPP +, paraquat, rotenone, and permethrin (Prasad and Hung, 2020). In 2008, Bouchez et al. used a rat model of PD to show that MSCs could improve motor function when injected into the rat brains (Bouchez et al., 2008). Similarly to preclinical studies in rodent models of AD, MSCs in PD promote microglial autophagy which clears a-synuclein plaques, possibly through the activity of Beclin-1, and enhance cellular viability (Park et al., 2014; Chen H. X. et al., 2020). Furthermore, Schwerk et al. reported that AD-MSCs increased sub-ventricular zone neurogenesis in a rat model of PD, an area of the brain associated with the sleep disturbances observed in early PD (Schwerk et al., 2015).

Similarly to animal models of AD, dextran-coated IONPs have been employed to help target MSC therapies to the substantia nigra. Chung et al. found that loading MSCs with dextran-coated IONPs improved homing to dopaminergic lesions and induced dopaminergic-like differentiation of MSCs in a mouse model of PD (Chung et al., 2018). Use of magnetic resonance-guided focused ultrasound techniques to transiently disrupt the BBB has also shown promising results in improving MSC delivery to the brain in rat models of PD (Wu S. K. et al., 2025).

The first use of MSCs in clinical trials of PD was reported in 2010 by Venkataramana et al. (2010). 7 patients underwent unilateral implantation of autologous BM-MSCs in the sublateral ventricular zone. 3 patients demonstrated continuous clinical improvement with no serious adverse events (Venkataramana et al., 2010). The same research group conducted a similar study with allogenic BM-MSCs transplanted bilaterally in the subventricular zone and reported positive results. Notably, patients in this trial who had PD for less than 5 years experienced greater clinical effects, with more advanced cases showing no clinical improvement (Venkataramana et al., 2012).

More recent clinical trials have expanded on the efficacy and mechanism of action of MSCs in treating PD. A phase 1 dose-escalation study (NCT02611167) using allogenic BM-MSCs reported a lack of serious treatment-related adverse events in addition to a decrease in TNF-α, Chemokine Ligand 22, and an increase in BDNF in the highest dose. This modulation of inflammatory factors was correlated with greater clinical benefit as measured by the UPDRS (Schiess et al., 2021). Preliminary results from a phase 2 trial (NCT04506073) suggest that motor improvements in patients treated with allogenic BM-MSCs are associated with lower levels of serum neurofilament light chain (NfL) (Lemus et al., 2025), a marker of neuronal damage (Gaetani et al., 2019).

Upcoming clinical studies feature alternative administration strategies and MSC treatment formulations. A phase 1/2 trial (NCT03684122) in 10 patients with PD is investigating a combination of hUC-MSCs and hUC-MSC-derived neural progenitor cells administered either intravenously or intrathecally + intravenously. Results on this trial are still forthcoming (Jamali et al., 2021). A currently active phase 2 trial (NCT04995081) is using allogenic AD-MSCs in 60 patients with mild-to-moderate PD. 6 intravenous infusions will be performed at 4-week intervals with the logic that repeated exposure to MSCs will enhance their therapeutic effect. This trial is expected to be completed in 2026. A phase 1 study scheduled to start in 2026 (NCT05094011) will investigate the safety and efficacy of stereotactic intrastriatal AD-MSCs in 9 patients with idiopathic PD. An upcoming phase 1/2 trial (NCT06858254) will investigate a combined intranasal and intravenous approach in patients with either PD or Parkinson’s Disease plus (PPS). Additionally, a phase 1 study scheduled for completion in 2027 (NCT05152394) will report on the efficacy of hUC-MSC-derived exosomes in improving symptoms of PD. A summary of clinical trials for PD using MSCs are presented in Table 2.

Early preclinical trials studying MSCs in models of ALS primarily utilized SOD1-G93A mice (Zhao et al., 2007). These mice carry a pathogenic form of the SOD1 gene which leads to the development of ALS (Chia et al., 2018). MSCs have been shown to slow neuronal and axonal degeneration in ALS, slow motor function deterioration, extend lifespan, and attenuate microglial and astrocyte activation in SOD1-G93A mice (Zhao et al., 2007; Vercelli et al., 2008; Kim H. et al., 2010). Though these studies were the first to demonstrate the efficacy of MSCs in treating ALS, in both experiments the MSC treatment was administered in pre-symptomatic mice. Early intervention before symptoms appear is uncommon in the traditional healthcare setting because symptoms onset is slow and non-specific (Feldman et al., 2022).

Studies performed in symptomatic animal models of ALS yielded similar results (Boucherie et al., 2009; Uccelli et al., 2012; Marconi et al., 2013), suggesting that MSCs are effective in treating ALS even when administered after symptom onset. Exosomes derived from MSCs have also shown promising neuroprotective benefit both in vitro and in vivo models of ALS (Bonafede et al., 2016; Bonafede et al., 2020).

The first study to demonstrate that MSC treatment for ALS was feasible in human subjects was reported on by Mazzini et al. in 2003. The authors reported no adverse events in 7 patients transplanted intrathecally with autologous BM-MSCs (Mazzini et al., 2003). However, due to the small sample size, no conclusions could be made as to the efficacy of the treatment. Two follow-up clinical trials were conducted by Mazzini to further investigate the safety and characterize the effects of MSC treatment in ALS patients (Mazzini et al., 2010; Mazzini et al., 2012). The first study in 10 patients with ALS treated intrathecally with autologous BM-MSCs reported no serious treatment-related adverse events (Mazzini et al., 2010). The second study was a longitudinal follow-up study in the 19 patients enrolled in the first two phase 1 clinical trials. After a 9-year follow-up period the treated patients demonstrated no abnormal structural changes in the brain or spinal cord and no decline in psychological status. However, no clinical improvement was noted (Mazzini et al., 2012). Despite lack of clear therapeutic benefit, these studies were the first to prove that MSC treatment for ALS is safe and feasible both in the short- and long-term.

Another early phase clinical trial (NCT00855400) conducted by Blanquer et al. adopted the approach used by Mazzini et al. to investigate autologous BMMNCs in the treatment of ALS (Blanquer et al., 2012). 11 ALS patients were injected intrathecally BMMNCs following laminectomy. In 1 year of follow up no serious treatment-related adverse events were recorded and no increase in clinical rate of decline was reported. Histological examination of the spinal cord of 4 patients who passed away due to causes unrelated to treatment revealed a higher density of motoneurons in regions of the spinal cord injected with BMMNCs, and these motoneurons exhibited fewer intracellular TDP-43 deposits. Interestingly, a number of surviving motoneurons were surround by CD90 + cells, and these motoneurons displayed no TDP-43 reactivity, suggesting that CD90 + cells may exert a neuroprotective effect in ALS by preventing TDP-43 aggregation or enhancing clearance (Blanquer et al., 2012). Overall, this study provided evidence for the neuroprotective effect of BMMNCs in ALS in humans.

Not long after, a phase 1/2 and 2a clinical trial (NCT01051882 and NCT01777646) conducted by Petrou et al. in 28 patients administered NurOwn^® cells (autologous BM-MSC-NTF cells) both intramuscularly and intrathecally reported that the treatment was safe and modestly effective in slowing motor decline (Petrou et al., 2016). The cells used in this trial had been specifically cultured to produce neurotrophic factors to promote cell survival and endogenous mechanisms of recovery (Gothelf et al., 2014). The results of a larger phase 2 trial enrolling 48 patients indicate that treatment with NurOwn^® cells was capable of delaying the clinical course of ALS in a predefined rapidly progressing subset of patients (Berry et al., 2019).

Petrou would conduct another (NCT04821479) focused on repeat injection of autologous BM-MSCs. 20 patients with ALS were administered up to 4 intrathecal injections of autologous BM-MSCs. No serious adverse events were reported, and the treatment was found to be effective after just 1 injection (Petrou et al., 2021). There was significant participant drop-off and loss to follow up, but patients who remained in the study experienced a significant improvement in the rate of progression of ALS when measured using the ASLFRS-R (Petrou et al., 2021).

A phase 3 study (NCT03280056) investigating NurOwn^® cells was recently completed. 196 patients with ALS were administered either the MSC treatment or placebo via intrathecal injection. The treatment was well-tolerated, but the primary efficacy endpoint, change in ALSFRS-R progression compared to controls at 28 weeks, was not statistically significant. However, MSC treatment reduced markers of neuroinflammation and neural damage while increasing levels of neurotrophic factors in the CSF (Cudkowicz et al., 2022). It was theorized that the therapy may be more effective in treating early/mild ALS, so a follow-up phase 3 clinical trial (NCT06973629) in early symptomatic ALS and moderate ALS was initiated and is scheduled to be completed in 2028. Another phase 3 trial (NCT04745299) investigating autologous BM-MSCs is currently in progress and scheduled to be completed in 2026. This study plans to enroll 115 patients w/either familial or sporadic ALS. Patients in the single cycle administration group will be given two injections of MSCs within 26 days, and patients in the multiple administrations group will be given 2 injections in 26 days followed by 3 repeat injections every 3 months. Additionally, each patient will be administered riluzole for the study duration. These larger trials will provide data on the efficacy of MSC treatments for ALS.

Two upcoming registered clinical trials plan to study the MSC secretome in ALS patients. The phase 1 basket-design clinical trial (NCT06607900) discussed earlier will include an ALS arm. Another phase 1/2 placebo-controlled clinical trial (NCT06598202) will use hUC-MSC exosomes to treat early-stage ALS (< 2 years) in 38 patients. This study is expected to be completed in 2026. Table 3 includes a summary of completed and upcoming clinical trials of MSCs for PD.

Preclinical studies of MS have historically used an experimental autoimmune encephalitis (EAE) model. EAE is an artificial autoinflammatory condition created by sensitizing the host immune system to autoantigens, thereby activating the immune system against itself (Constantinescu et al., 2011). The EAE model has been used for decades to study a variety of autoinflammatory nervous system disorders (Rivers et al., 1933; Rivers and Schwentker, 1935).

The first preclinical trial studying the potential of MSCs in treating EAE was conducted in Zappia et al. (2005). This study induced EAE using myelin oligodendrocyte glycoprotein 35-55 (MOG35-55). EAE mice were treated intravenously with BM-MSCs. Treated mice experienced profound reduction in EAE severity without inducing tumorigenicity or immunodeficiency. Evidence collected on T-cell activity during the study demonstrated significant reduction in T-cell proliferation when treated with BM-MSCs (Zappia et al., 2005), which is consistent with evidence reported from previous in vitro models (Bartholomew et al., 2002). It should be noted that the mice in this study were administered BM-MSCs at either the onset of symptoms or during the peak of symptom severity, as opposed to after resolution of symptoms, a method which has become standard practice (Zappia et al., 2005; Kurte et al., 2015).

Further analysis of the immunomodulatory effects of MSCs in subsequent preclinical models of MS revealed that MSCs reduce T-cell secretion of TNF-α and IFN-γ and reduce T-cell proliferation upon contact with antigen (Gerdoni et al., 2007). Furthermore, BM-MSC transplantation in an EAE model of MS reduced mortality to 0% (Kassis et al., 2008). These results were consistent with those reported by Zappia et al. (2005). These studies together provided strong evidence that MSCs could serve as a potential treatment for MS in humans.

MSCs have been shown to be moderately effective in treating MS in human clinical trials. A meta-analysis of the clinical trials involving MSCs in treating MS conducted in 2023 showed that about 40% of MS patients treated with MSCs saw improvement. 32.8% remained stable, and 18.1% worsened. Headaches and fevers were the most common side effects. These data suggest that MSC therapy for MS is overall safe in humans and shows therapeutic promise (Islam et al., 2023).

The first clinical trials in humans investigating the potential of MSCs for treating MS were conducted in the mid-2000s. In the first study investigators treated 5 patients with SPMS with autologous BM-MSCs via intrathecal route. The treatment was deemed safe, but few patients experienced clinical benefit as measured by the Expanded Disability Scale Score (EDSS) (Mohyeddin Bonab et al., 2005). A follow up study was conducted in 10 patients with PPMS or SPMS. These patients were also treated with autologous BM-MSCs, but only a minority experienced clinical benefit (Mohyeddin Bonab et al., 2007). These studies provided the first in human evidence for the feasibility of MSC therapy for patients with MS.

A phase 2 clinical trial based on these initial studies was later conducted by the same research group (Bonab et al., 2012). In this study, 25 patients with MS were injected intrathecally with autologous BM-MSCs and monitored for 1 year. No serious adverse events were reported, but only 4 patients experienced clinical improvement in the EDSS, whereas 6 patients experienced in a decline in the EDSS. Additionally, 6 patients demonstrated new or worsening lesions on magnetic resonance imaging (MRI) (Bonab et al., 2012).

The results of another early phase 1 study published in 2010 confirmed the safety of autologous BM-MSCs for treating MS (Yamout et al., 2010). 10 patients with advanced MS were administered autologous BM-MSCs intrathecally and followed up for 1 year. EDSS metrics revealed improvement in 5 of the 7 patients, but MRI indicated worsening lesions in 5 of the 7 patients as well (Yamout et al., 2010), consistent with other trials (Bonab et al., 2012). The only serious adverse event was transient encephalopathy with seizures in 1 patient (Yamout et al., 2010).

Karussis et al. published the results of a phase 1/2 clinical trial (NCT00781872) in the same year which featured both an ALS treatment group (n = 19) and an MS treatment group (n = 15) (Karussis et al., 2010). They transplanted 15 MS patients with BM-MSCs both intrathecally and intravenously and observed no serious adverse events. The mean EDSS score of patients improved and markers of immune cell activation and proliferation were reduced. Notably, peripheral CD4 + and CD25 + regulatory T-cell populations in the blood were increased following MSC administration (Karussis et al., 2010). This is consistent with evidence from preclinical trials that MSCs target and regulate the adaptive immune system (Zappia et al., 2005; Gerdoni et al., 2007).

A phase 1/2 clinical trial (NCT00395200) published in 2012 treated 10 patients with SPMS and evidence of optic nerve involvement with autologous BM-MSCs. No serious adverse events were reported from intravenous administration. The Investigators found that on average patients treated with autologous BM-MSCs experienced higher visual acuity scores and visual evoked response latency compared to baseline in addition to increased optic nerve area (Connick et al., 2012). These results suggest that MSCs can improve visual symptoms in MS.

Two clinical trials conducted by Harris et al. would investigate the use of MSC-derived neural progenitor cells (MSC-NP) in patients with progressive MS. MSC-NP cells are a subtype of MSC which exhibit neural characteristics (Harris et al., 2012). In 2016, the results of a pilot study in 6 patients with MS were reported, which showed promising safety and efficacy results. No serious adverse events were reported, and 4 of the 6 patients experienced improvement on the EDSS relative to baseline (Harris et al., 2016). In 2018 the results of a full phase 1 study (NCT01933802) in 20 patients with progressive MS were reported. The researchers administered 3 intrathecal doses of MSCs and observed no serious treatment-related adverse events and reported measurable improvements in several patients in EDSS scores, muscle group strength, and bladder symptoms (Harris et al., 2018).

The results of a large phase 2 trial (NCT02239393) conducted by Uccelli et al. were reported in 2021. 144 patients with MS were treated intravenously with autologous BM-MSCs. No treatment-related serious adverse events were reported, but ultimately the trial did not meet the primary efficacy endpoint of reducing gadolinium-enhancing lesions (GEL) on MRI (Uccelli et al., 2021). Another phase 2 trial (NCT03799718) investigated the safety of NurOwn^® cells in treating PPMS and SPMS. 18 patients with PPMS or SPMS were treated with 3 intrathecal injections of NurOwn^® cells (17 patients received all 3 injections). 7 serious treatment-related adverse events were reported. Several patients observed improvements in motor symptoms (Cohen et al., 2023), but larger studies with control comparison are needed to further investigate these cells.

Though most of the clinical trials utilizing MSCs to treat MS have employed BM-MSCs, other sources of MSCs have been investigated. Multiple studies (NCT05116540, NCT0105647) have employed AD-MSCs in clinical trials, but despite their good safety profiles, these trials have failed to demonstrate significant clinical improvement (Fernández et al., 2018). Additionally, several trials have investigated hUC-MSCs or placenta-derived MSCs for MS with mixed results (Li et al., 2014; Lublin et al., 2014).

There are several upcoming clinical trials for MSCs in MS. A phase 1/2 clinical trial (NCT04749667) is currently active and aims to enroll 18 patients with primary or SPMS. These patients will be administered autologous BM-MSCs via intrathecal injection. Two clinical trials are in the recruiting phase. The first is a phase 1 study (NCT05003388) which will investigate the safety of allogenic hUC-MSCs in patients with MS. The second is a phase 1/2 trial (NCT05532943) which will recruit 41 patients with RRMS or SPMS. Patients will be administered allogenic hUC-MSCs through intravenous infusion day 0 then again 28 days later via intrathecal infusion. Both studies are expected to be completed in 2025 and 2026 respectively.

The evidence that has been reported from these clinical trials clearly shows the safety of multiple types of MSCs for treating both relapse-remitting and progressive MS, but the current lack of phase 3 clinical trials indicates the need for larger, randomized, placebo-controlled trials to further characterize the efficacy and mechanism of action of MSCs in MS. Table 4 summarizes the findings of clinical trials studying MSCs for therapeutic use in MS.

Early preclinical studies showed that MSCs were safe and effective in treating stroke. One of the first studies to use MSCs in a preclinical model of stroke demonstrated that BM-MSCs injected intravenously improved outcomes over controls. Interestingly, the authors also observed that MSCs migrated to the brain but remained mostly undifferentiated (Chen et al., 2001). The authors hypothesized this could be due to the production of cytokines and trophic factors which boost endogenous mechanisms of regeneration, which is consistent with a paracrine signaling mechanism of action (Chen et al., 2001). Shortly following this study, Kang et al. used human AD-MSCs induced toward a neural cell morphology in rat MCAO stroke models and observed improved outcomes. These findings were enhanced when the MSCs were transduced to express BDNF, demonstrating the viability of MSCs as delivery vehicle for trophic factor secretion in neurologic disease (Kang et al., 2003). A long-term follow-up study in a rat model of stroke reported that MSCs promote neurologic recovery as long as 1 year post-MCAO (Shen et al., 2007).

For stroke in particular, the timing of treatment is of great concern. Traditional thrombolytic and clot retrieval therapies must be administered in under 4.5 h which is often unattainable in clinical practice (Cunningham et al., 2018). A preclinical study by Toyoshima et al. demonstrated that the optimal timing of allogenic MSC administration for MCAO models of stroke was 24 h (Toyoshima et al., 2015), though other studies suggest that MSCs remain beneficial as long as 3 days after MCAO (Cunningham et al., 2018). Another study reported that two infusions of MSCs at 8 and 24 h post stroke was more efficacious than a single infusion at 24 h, which supports a multiple-dose treatment strategy (Kranz et al., 2010). While the optimal time and dosing strategy is still up for debate, it is clear that MSC infusion following stroke has a longer effective time frame than conventional therapies while still providing significant neurological recovery.

MSC exosomes have also shown therapeutic benefit in preclinical models of stroke. The first preclinical study to investigate exosomes in the treatment of stroke was performed by Xin et al. (2013a). The investigators treated MCAO rats with 100 μg of BM-MSC-derived exosomes 24 h post-MCAO. They found that rats treated with BM-MSC-exosomes showed significant improvement in motor function and improved neurogenesis, angiogenesis and enhanced neural remodeling (Xin et al., 2013a). Doeppner et al. confirmed these findings by comparing human BM-MSC-derived exosomes to human BM-MSCs in a mouse MCAO model. The BM-MSC exosomes exerted a similar effect to the MSCs in vivo, making this one of the first studies to demonstrate the efficacy of ex vivo harvested MSC-derived exosomes alone in the treatment of ischemic stroke (Doeppner et al., 2015). Another combinatorial strategy found that BMSC exosomes combined with rosuvastatin in rats decreased infarcted lesion size and reduced glial scarring (Safakheil and Safakheil, 2020).

The earliest clinical trial investigating the use of MSCs for the treatment of ischemic stroke was reported in 2005. In this study 5 patients treated with autologous BM-MSCs demonstrated improvements on the Rankin score and Barthel Index (BI) with no treatment-related adverse events (Bang et al., 2005). A 5-year follow-up trial involving 52 patients found that the treatment group had lower overall mortality compared to the control group, while no differences in comorbidities between groups were observed during the follow-up period (Lee et al., 2010).

Another notable clinical trial evaluating autologous BM-MSCs administered to 12 stroke patients between 36 and 133 days post-stroke reported over 20% lesion volume reduction (Honmou et al., 2011). Concurrent trials confirmed the safety of BM-MSCs for use in treating stroke patients. Bhasin et al. reported no treatment-related adverse events but only slight improvements (Bhasin et al., 2011); however, a second trial showed no adverse reactions with a statistically significant improvement on the modified Barthel Index (mBI) in the treated group (Bhasin et al., 2013).

Recent clinical trials have explored alternative administration routes and innovative stem cell formulations. A notable phase 1/2 dose-escalation trial (NCT01287936) administered BM-MSCs transfected with the Notch-1 gene via stereotactic implantation in chronic ischemic stroke patients. Transfection with the Notch-1 plasmid is transient, and transfected cells do not survive overlong in vivo, minimizing risk of unanticipated side effects from Notch-1 expression. Treated patients experienced clinically meaningful improvements (Steinberg et al., 2016), thus confirming the feasibility of transiently manipulated MSCs for human stroke treatment. Another phase 2 clinical trial (NCT04811651) investigating the efficacy of allogenic hUC-MSCs against placebo in 156 patients with acute stroke has been recently completed, but to our knowledge results have not yet been published.

The first phase 3 clinical trial (NCT01716481) of MSCs in stroke patients was conducted in South Korea from 2012 through 2017. Autologous BM-MSCs preconditioned with post-stroke autologous serum were administered intravenously in 54 patients with acute ischemic stroke. Despite a positive safety profile, no significant therapeutic efficacy was demonstrated (Chung et al., 2021). Similarly, a sequence of clinical trials investigating the allogenic bone marrow-derived mesenchymal progenitor cell product MultiStem HLCM501 (allogenic BM-multipotent progenitor cells) have shown positive safety data but failed to yield significant clinical results (Hess et al., 2017; Houkin et al., 2024). These trials have culminated in a phase 3 clinical trial (NCT03545607), but the status of this trial remains unknown.

Emerging trials have targeted different forms of stroke. In 2022 Baak et al. published results from a phase 1/2 study (NCT03356821) investigating intranasal allogenic BM-MSC administration for perinatal arterial ischemic stroke. Results showed promising safety but no significant clinical improvements (Baak et al., 2022). Additionally, a small phase 1 trial (NCT03371329) in patients with acute intracerebral hemorrhage demonstrated MSC treatment feasibility along with increased anti-inflammatory cytokines CD40L, IL-1RA, and IL-10 up to 3 days after treatment, suggesting that MSCs may attenuate acute inflammation in hemorrhagic stroke (Durand et al., 2024).

There are a number of upcoming and in-progress clinical trials involving MSCs for stroke treatment. A phase 2/3 study (NCT06129175) will investigate allogenic hUC-MSCs in 80 patients with acute stroke. A phase 1/2 study (NCT06997939) investigating autologous BM-MSCs was recently registered. This study plans to recruit 12 patients with ischemic stroke and measure the efficacy of Ommaya drug reservoir administration versus internal carotid artery transplantation. Notably, two upcoming clinical trials plan to study the therapeutic efficacy of MSC-exosomes for stroke. The first (NCT05158101) will study exosomes derived from allogenic hUC-MSCs. 15 stroke patients will be recruited, and 2 doses of approximately 800 billion exosomes will be administered intranasally. This trial is expected to conclude in 2026. Another phase 1 clinical trial (NCT06995625) will study allogenic WJ-MSC exosomes in the treatment of ischemic stroke. This study will treat 18 patients in a dose escalation design to determine the maximum tolerated dose. This study is expected to be completed in 2027. Table 5 provides a summary of clinical trials investigating MSCs for treatment of stroke.

In vitro and animal models have served as vital tools for studying the beneficial effects of MSCs in treating SCI since the early 2000s. The first study to demonstrate SCI-specific safety and feasibility of MSCs was conducted by Chopp et al. (2000) using a rat model SCI induced via weight drop method. The MSC treatment showed significant functional improvement in the injured rats, and the authors theorized that the MSCs could be acting through a paracrine signaling mechanism (Chopp et al., 2000), a theory that would be explored as the field evolved (Liu et al., 2019).

Since the characterization of their therapeutic benefit in SCI, another promising avenue of research in preclinical studies is the adjunctive use of hydrogels and collagen scaffolds alongside MSC transplantation, which can improve MSC survival and efficacy (Lv et al., 2021; Pang et al., 2021; Silva et al., 2021). In an experiment by Papa et al. a biomimetic hydrogel scaffold was loaded with hUCB-MSCs and grafted into a mouse model of SCI. The engrafted mice showed improved cytoskeletal architecture preservation, increased neuronal survival, and M2 macrophage proliferation, likely through the release chemokine ligand 2 (CCL2) (Papa et al., 2018). The same result was observed in canine models of SCI which showed axonal regeneration following hUC-MSC impregnated collagen scaffolds surgically implanted into the thoracic spinal cord of canines (Li et al., 2017).

In addition to scaffolds, the combination of MSCs with pharmaceuticals and/or genetically altered MSCs has emerged as a promising therapeutic strategy. One such study by Lee et al. combined AD-MSCs with chondroitinase ABC (chABC), an enzyme capable of breaking down chondroitin sulfate proteoglycan (CSPG) glial scars, which improved SCI functional outcomes in canines (Lee et al., 2015). AD-MSCs engineered to express chABC also yielded significant functional improvements in rat models of SCI (Lu et al., 2020). Furthermore, hUC-MSCs transduced with an IL-10-producing-vector improved functional outcomes, reduced lesion size, and improved axonal regeneration in mice (Gao et al., 2022). The same was true of MSCs engineered to overexpress IL-13 (Dooley et al., 2016).

There have been many attempts to translate the results of preclinical trials of MSCs in SCI to human trials with mixed results. Early treatment approaches with MSCs primarily employed BMMNCs and yielded promising results (Chernykh et al., 2007; Yoon et al., 2007; Kumar et al., 2009). Subsequent MSC-specific clinical trials demonstrated consistent safety data across a range of MSC sources. One phase 1 trial (NCT01274975) used autologous AD-MSCs in 8 patients with SCI and observed no adverse events or tumorigenicity (Ra et al., 2011). Another phase 1 trial (NCT01325103) in 14 subjects investigated BM-MSCs demonstrated improvement in AIS scores and urologic function (Mendonça et al., 2014).

More recent clinical trials have supported the safety and modest efficacy of MSCs in SCI (Oh et al., 2016; Satti et al., 2016; Yang et al., 2021). A phase 1 study (NCT02482194) in 9 patients administered BM-MSCs through intrathecal injection showed no treatment-related adverse events (Satti et al., 2016). A phase 1/2 clinical trial (NCT02481440) using allogenic hUC-MSCs in 102 patients with SCI at various locations also showed no serious treatment-related adverse events and even demonstrated improvements in ASIA and IANR-SCIFRS scores (Yang et al., 2021). Most notable, perhaps, is the CELLTOP trial, a phase 1 clinical trial (NCT0330856) in ten patients treated with autologous AD-MSCs. A preliminary report on the progress of the first patient in the study, who suffered an AIS grade A C3-C4 SCI, detailed remarkable clinical improvement (Bydon et al., 2020), which generated considerable excitement about the potential of AD-MSCs for treating SCI. The results from the full phase 1 trial (NCT03308565) described improvement in AIS score in 7 of the 10 participants (Bydon et al., 2024).

A pilot study in 10 patients with ASIA grade A or B demonstrated that intramedullary injection of BM-MSCs during laminectomy followed by 2 subsequent intrathecal injections of BM-MSCs improved long-term motor function in 3 patients and reduced glial scar formation in 2 patients (Park et al., 2012), a phenomenon consistent with preclinical studies (Anjum et al., 2020). A phase 2/3 clinical trial (NCT01676441) was initiated based on the results of this pilot study. The same procedure of intramedullary injection following laminectomy was employed, but only one injection was performed due to restrictions around multiple administrations for phase 3 trials. The trial ultimately failed to meet its efficacy endpoint, possibly due to the reduction of treatment rounds (Oh et al., 2016).

Studies that followed have continued to demonstrate the safety and potential of MSCs in treating SCI. A phase 1/2 study of allogenic WJ-MSCs in 10 patients (NCT03003364) with thoracic SCI showed significant improvement in pinprick sensation below the level of injury and a reduction in bladder symptoms (Albu et al., 2021). Similarly, a phase 1/2 repeat dose study (NCT02981576) investigating the efficacy of BM-MSCs vs. AD-MSCs intrathecal injections in 14 patients showed improvements in 4 patients, and one patient even regained the ability to walk (Jamali et al., 2024). Notably, a phase 1 clinical trial (NCT02352077) provided first in-human evidence for the use of collagen scaffold (NeuroRegen) use alongside MSCs. In this study 8 patients with SCI received surgical implantation of a scaffold loaded with hUC-MSCs. The majority of patients experienced an expansion of sensation level and motor-evoked potential (MEP) responsive area, but no overall improvement was seen in ASIA scores (Zhao et al., 2017). Another clinical trial using NeuroRegen scaffolds loaded with BMMNCs in combination with a 6-month course of standardized rehabilitation showed sensory improvement, but no motor improvement. A follow-up study (NCT02688049) investigating the NeuroRegen scaffold in combination with either MSCs or neural stem cells has been initiated, but the status of this trial remains unknown.

There are three notable upcoming clinical trials studying MSCs for SCI. A phase 1 trial (NCT05018793) will recruit 15 patients with SCI and compare the efficacy of autologous AD-MSCs against allogenic hUC-MSCs. The CELLTOP part II trial (NCT04520373) will enroll 40 patients with SCI and compare the efficacy of autologous AD-MSCs to best medical management, alongside occupational and physical therapy. Finally, a phase 1/2 trial (NCT06981338) will combine allogenic WJ-MSCs with transcutaneous spinal cord stimulation and neurorehabilitation for the first time in humans. Table 6 describes the current state of clinical trials involving MSCs for treatment of SCI.

While other types of stem cells have shown benefit in treating TBI, the first preclinical trial of specifically BM-MSCs in treating TBI was conducted by (Mahmood et al. (2001). Despite the positive motor function results of the study, the mechanism of therapeutic effect was not fully explored (Mahmood et al., 2001). Subsequent work has suggested that MSCs primarily operate through paracrine signaling upon administration; however, there is conflicting evidence from other preclinical studies suggesting that intravenous injection of MSCs may not be as effective as other routes of administration (Harting et al., 2009). MSCs may also target the pathological build-up of tau post TBI. Tau accumulation in the TBI brain follows a unique pattern whereby it selectively deposits in perivascular regions within the sulci of the brain (McKee et al., 2009). A recent study investigating MSC-exosomes in a mouse model of TBI provided evidence that MSC-exosomes could reduce tau burden after TBI. The TBI mice were administered human BM-MSC-derived-exosomes loaded with anti-cis phosphorylated tau (p-tau) antibodies. Lower levels of cis p-tau, and cleaved caspase-3 as well as higher levels of p-PI3K were observed, which correlated with greater functional recovery (Amini et al., 2023). While MSCs have been shown to improve clearance of Aβ in AD models (Lee et al., 2009; Qin et al., 2022), Aβ deposition, while frequent in TBI, is less strongly associated with TBI (McKee et al., 2009), thus Aβ clearance may not be a primary mechanism by which MSCs exert their therapeutic effect.

The first major clinical trial investigating the safety and efficacy of BMMNCs for treating TBI was conducted by Cox et al. in pediatric patients (NCT00254722). 10 pediatric patients from 5-14 years old were administered autologous BMMNCs intravenously within 48 h of TBI. The treatment was well-tolerated overall with no detectable treatment-related toxicities (Cox et al., 2011). A retrospective cohort study performed with the data from this trial also showed that autologous BMMNC treatment following TBI reduced the intensity of medical therapy in the intensive care unit compared to controls (Liao et al., 2015). Following this study, Cox et al. conducted a placebo-controlled clinical trial (NCT01575470) using autologous BMMNCs administered in adults within 48 h after TBI. Autologous BMMNC treatment was safe and even reduced levels of inflammatory cytokines relative to controls (Cox et al., 2017). BMMNCs may also improve outcomes in chronic TBI. Sharma et al. reported the results of a pilot study on autologous BMMNCs administered intrathecally in 14 patients with chronic TBI. 14 patients were recruited and administered BMMNCs intrathecally alongside a course of neurorehabilitation therapy. Multiple participants experienced improvements in various domains of motor function and activities of daily living (Sharma et al., 2015). Though this study yielded promising results, larger, controlled studies will be needed to fully characterize the activity of BMMNCs in chronic TBI.

In 2013, Wang et al. reported the results of controlled clinical trial in 40 patients with sequelae of TBI between 1 and 11 years after injury. Patients were administered allogenic hUC-MSCs intrathecally. Fugl-Meyer Assessment (FMA) and Functional Independence Measure (FIM) scores were obtained at baseline and after 6 months of follow-up. Treated participants demonstrated clinical improvement in motor function and independence as measured by the FMA and FIM respectively, whereas controls exhibited no clinical improvement (Wang et al., 2013). This study provided strong evidence that hUC-MSC therapy is beneficial in treating chronic TBI.

One recent phase 2 clinical trial (NCT02416492) investigated the efficacy of modified MSCs in patients with TBI. 46 patients in the treatment group underwent stereotactic implantation with allogenic BM-MSCs transiently modified with a Notch-1 plasmid, which inhibited their ability to differentiate into other cell types. Only 1 patient in the treatment group experienced a serious treatment emergent adverse event possibly related to the cell treatment. Overall, the treatment was shown to significantly improve motor function compared to controls as measured by the Fugl-Meyer motor score (Kawabori et al., 2021). The results of another phase 2 trial using autologous BMMNCs were recently reported by Cox et al. (2024) (NCT01851083). This trial expanded on a previous phase 1 trial (Cox et al., 2011) by implementing a randomized, double blind, placebo-controlled design. 47 pediatric patients with acute TBI (< 48 h) and GCS score 3-8 were recruited. Patients treated with autologous BMMNCs experienced shorter time on the ventilator and in the intensive care unit (Cox et al., 2024), which is consistent with previous results (Liao et al., 2015). The treatment group also displayed greater white matter and corpus collosum preservation compared to controls after 1 year post-treatment (Cox et al., 2024).

A number of clinical trials are currently ongoing. A phase 2 clinical trial (NCT05951777) scheduled for completion in 2026 will investigate the safety of autologous AD-MSCs in patients with TBI. Another phase 1 trial (NCT05018832) scheduled to be completed by 2028 will investigate the safety of allogenic hUC-MSCs in patients with chronic TBI. Finally, a phase 1/2 trial investigating autologous AD-MSCs (NCT04063215) was recently completed in 2024, but results are still under review.

It must be noted that acute and chronic phase TBI are distinguished by unique mechanisms of cell death and neuroinflammation and may respond to MSC therapy differentially. The majority of clinical trials have focused on chronic phase TBI, whereas fewer have focused on acute TBI, and only one completed study has focused on acute TBI in adults, though we are still awaiting results from NCT02525432. Similarly to stroke, it is logistically challenging to intervene in the acute phase of injury, but evidence from preclinical studies shows that expeditious administration of cell-based therapies results in greater clinical recovery. Table 7 describes completed and ongoing clinical trials of MSCs in TBI.

BM-MSCs and AD-MSCs are capable of differentiating into the NP phenotype (Richardson et al., 2006; Clarke et al., 2014; Richardson et al., 2016). A number of preclinical trials have shown that MSC transplantation in DDD can increase aggrecan expression and matrix production (Sakai et al., 2005; Feng et al., 2011; Chun et al., 2012; Marfia et al., 2014), which may lead to an increase in disc height due to rehydration of the disc (Jeong et al., 2009). MSC transplantation may also induce NP cells to suppress MMP and inflammatory cytokine genes (Miyamoto et al., 2010). Altogether, these preclinical trials suggest that MSCs target the deleterious mediators of inflammation and matrix destruction as well as promote matrix repair and rehydration.

MSC-derived exosomes alone also exert many of the same effects, increasing cell proliferation, hydration and extracellular matrix deposition while reducing oxidative stress, attenuating inflammation, and preventing apoptosis of cells within the disc (Bhujel et al., 2022). Additionally, pre-treatment of hUC-MSCs to induce a chondrogenic progenitor-like phenotype showed enhanced improvement in DDD compared to untreated MSCs, potentially due to increased ability to differentiate into NP cells and ability to survive in the relatively hypoxic environment of the intervertebral disc (Ekram et al., 2021).

Clinical trials in DDD have demonstrated that BM-MSCs, and AD-MSCs are safe and quite effective in treating DDD. The first in-human evidence for the efficacy of MSCs in treating LBP was provided by Yoshikawa et al. (2010). 2 patients with lumbar spinal canal stenosis underwent surgical implantation of collagen sponges loaded with autologous BM-MSCs into the affected lumbar discs. The patients experienced lasting pain relief at 2 years post-surgery and notable disc rehydration on T2-weighted MRI (Yoshikawa et al., 2010).

Orozco et al. followed this up with a larger study in 10 patients with LBP due to lumbar disc degeneration (Orozco et al., 2011). Patients were treated with autologous BM-MSCs and reduction in pain and disability was measured via the visual analog scale (VAS) and the Oswerty Disability Index (ODI) respectively. Participants experienced reduction in LBP as early as 3 months post-treatment which persisted through 1 year of follow-up. They also experienced decreased disability status as assessed by the ODI. Though there was no improvement in disc height, the authors observed an increase in fluid content of the treated discs (Orozco et al., 2011). The strong safety and efficacy results of this clinical trial proved the feasibility of MSC transplantation for DDD and suggested that MSCs rehydrate degenerating discs, which is consistent with the data from Yoshikawa et al. (2010) and previous preclinical trials (Jeong et al., 2009; Marfia et al., 2014)

The same research group conducted a follow-up phase 1/2 clinical trial (NCT01860417) from 2013-2015 to test the efficacy of allogenic BM-MSCs, rather than autologous BM-MSCs, in the treatment of DDD (Noriega et al., 2017). Pain scores on the VAS improved at 3 months but declined from peak relief by 12 months. ODI scores, while improved, did not match improvements observed from autologous BM-MSCs (Orozco et al., 2011; Noriega et al., 2017). However, a subsequent long-term follow-up study from this trial reported that pain and disability scores continued to improve as long as 3.5 years after treatment in those patients administered allogenic BM-MSCs compared to controls (Noriega et al., 2021), altogether providing convincing evidence for the long-term benefits of MSCs used to treat DDD.

A phase 1/2 clinical trial (NCT01513694) recently demonstrated the benefit of autologous BM-MSCs embedded within tricalcium phosphate for spinal fusion surgery outcomes. Patients underwent MSC implantation during posterolateral spinal fusion surgery and were monitored for 12 months. MSCs were shown to aid in L4-L5, and L5-S1 spinal fusion with no adverse events. VAS and ODI scores also improved after the surgery, and 9 patients demonstrated successful solid fusion of the spine (Blanco et al., 2019).

MSCs have also been studied in combination with plate-rich plasma (PRP), an autologous mixture of platelets, trophic factors, and cytokines already used as a treatment for DDD and other joint pathologies (Kawabata et al., 2023). A pilot study by Comella et al. (NCT02097862) recruited 15 patients with lumbar DDD and treated them with autologous AD-MSCs and PRP. The treatment was found to be safe and modestly effective in improving flexion and reducing subjective measures of pain (Comella et al., 2017). However, more studies are needed to characterize the cooperative effect of MSCs with PRP.

The strongest evidence supporting the therapeutic benefit of MSCs in DDD comes from a recently completed phase 3 trial (NCT02412735) conducted in 404 patients with chronic LBP. Patients were administered allogenic bone marrow-derived MSCs with or without hyaluronic acid. While the primary and secondary efficacy endpoints were not met, the investigators reported a strong reduction in LBP and ODI disability scores in all treatment groups. Furthermore, MSC + hyaluronic acid treatment resulted in a substantial reduction in LBP, especially in patients with LBP less than 68 months. In these patients, MSC treatment was also associated with greater functional improvement, quality of life, and less opioid usage. Though primary efficacy endpoints were not met, the results of this trial are promising and warrant further exploration in patients with chronic LBP less than 68 months (Beall et al., 2025).

A number of upcoming clinical trials for MSCs in DDD have been initiated. A phase 2 study (NCT004042844) in 99 patients with suspected discogenic back pain will administer autologous BM-MSCs cultured in hypoxic media, thus acclimating them to the physiologic environment of the intervertebral disc. Another phase 2 study (NCT05066334) will enroll 52 patients with DDD at multiple lumbar discs. Autologous MSCs will be administered to up to 3 disc segments.

Overall, these studies provide strong evidence that MSC can reduce pain, improve disability, and elicit disc rehydration in DDD. Table 8 includes a brief summary of clinical trials in DDD.

MSCs have already been shown to provide benefit in preclinical studies of sepsis (Krasnodembskaya et al., 2010; Mei et al., 2010; Jackson et al., 2016; Laroye et al., 2017; Morrison et al., 2017). The therapeutic benefit of MSCs in sepsis is thought to be derived from modulation of immune cells, promotion of bacterial autophagy and reduction of inflammatory mediators (Krasnodembskaya et al., 2010; Mei et al., 2010; Laroye et al., 2017). Both BM-MSCs and hUC-MSCs were found to induce CD3 + CD4 + and CD25 + T regulatory cells, which coincided with a downregulation in IL-6 and TNF-α (Chao et al., 2014)., suggesting potent immune regulation and suppression of damaging immune responses.

Another potential mechanism is the transfer of mitochondria from MSCs to host macrophages, thereby aiding the process of autophagy (Jackson et al., 2016; Morrison et al., 2017). These same mechanisms also enable MSCs to decrease the risk of organ failure from sepsis and septic shock (Laroye et al., 2017).

Preclinical models of meningitis have provided evidence for the beneficial effect of MSCs, and most have come from models of neonatal meningitis. Transplantation of human umbilical cord blood-derived MSCs in a newborn rat model of meningitis resulted in reduced bacterial growth rate and mortality. Levels of inflammatory cytokines IL-1α, IL-1β, IL-6, and TNF-α as well numbers of activated macrophages were reduced. Additionally, functional behavioral tests improved at a faster rate in rats treated with MSCs (Ahn et al., 2018). Additionally, concomitant treatment of bacterial meningitis in newborn rats with MSC-exosomes did not enhance bacterial clearance but did reduce neuroinflammation and neural apoptosis (Kim et al., 2022), suggesting that MSC exosomes exert a neuroprotective effect, but are not as effect in clearing the infection as MSCs themselves.

The source of MSCs appears to significantly influence outcomes in animal models of sepsis. A study directly comparing human BM-MSCs against hUC-MSCs showed significant improvement in survival and bacterial clearance in the BM-MSC-treated mice, but not in the hUC-MSC-treated mice. 7-day survival rate for mice treated with BM-MSCs was 64.71%, while the survival rate in the hUC-MSC group was 29.4% (Varkouhi et al., 2021). However, there is conflicting evidence that BM-MSCs and UC-MSCs are equally effective in regulating the immune response in animal models of sepsis (Chao et al., 2014), especially when administered within the right time frame (Gonzalez et al., 2020).

Models of sepsis also show improvement when treated with MSC-derived exosomes. Exosomes of MSCs have been shown to reduce bacterial load in sepsis-induced lung injury, kidney injury, cardiovascular injury, and liver injury (Cheng Y. et al., 2020). The improvement was found to be due in part to delivery of mRNA and miRNA to injured tissue, thereby increasing gene expression and enhancing phagocytosis of bacteria by macrophages and promoting an anti-inflammatory M1 phenotype while reducing cellular apoptosis (Lee et al., 2013; Monsel et al., 2015; Zhu et al., 2019). These studies suggest that MSC-derived exosomes may be more effective than whole-cell therapy in the treatment of sepsis due to their ability to deliver factors directly to target cells. Treatment of sepsis requires timely administration of therapy, and exosomes are stable when stored, allowing for quick use and lack of immunogenicity where allogenic MSCs may exacerbate an already unstable immune system (Cheng Y. et al., 2020).

Several clinical trials have proven the safety of MSCs in treating sepsis (Khosrojerdi et al., 2021). Two early phase 1 clinical trials conducted in the 2010s using allogenic MSCs reported good safety profiles in patients under septic shock (Galstian et al., 2015; McIntyre et al., 2018) with another phase 1/2 study having demonstrated improved short-term survival in patients treated up to 5 times with allogenic AD-MSCs within 9 days (Alp et al., 2022). Looking forward, one phase 2 study (NCT05969275) hopes to recruit 296 patients and investigate whether allogenic hUC-MSC transplantation reduces the need for ventilator support, renal replacement therapy, and vasopressors. Another phase 1 study (NCT06882811) aims to determine whether allogenic hUC-MSCs improve mortality rate at 28 days post-treatments.

While the therapeutic use of MSCs for sepsis has been widely characterized, it has been less well-studied in meningitis. Preclinical studies have demonstrated therapeutic potential (Ahn et al., 2018; Kim et al., 2022), but there have been no clinical trials for meningitis and MSCs registered on clinicaltrials.gov. However, given the pathological similarities between sepsis and meningitis, it is reasonable to think that MSCs could be safely and effectively used to ameliorate harmful inflammatory responses in meningitis as well as sepsis. Due to the heterogenous nature of sepsis and meningitis, a unified treatment has not yet been developed, but MSCs present a novel therapeutic opportunity for treating both sepsis and meningitis. Table 9 presents data from clinical trials in patients with sepsis treated using MSCs.