Abstract

Background: Traumatic brain injury (TBI) presents with associated neurologic and vascular damage triggers a chain of events that lead to a secondary brain injury. Proper prevention may limit undesirable outcomes. Mesenchymal stem cells (MSCs) and their secretome are promising therapeutic agents for a variety of neurological injuries, including TBI, due to their neuroprotective effects. This paper offers a concise overview of the use of MSCs and secretomes to prevent secondary brain injury and improve functional outcomes in TBI patients.

Methods: An electronic database search on PubMed, Cochrane, Scopus, and clinicaltrials.gov was performed to include all relevant studies. Our framework incorporates an analysis of preclinical and clinical studies investigating the effects of MSCs and secretome on clinically relevant neurological and histopathological outcomes.

Results: Immunomodulation by molecular factors secreted by MSCs is considered to be a key mechanism involved in their multi-potential therapeutic effects. Regulated neuroinflammation is required for healthy remodeling of the central nervous system during development and adulthood. Moreover, immune cells and their secreted factors can also contribute to tissue repair and neurological recovery following acute brain injury. The use of secretome has key advantages over cell-based therapies, such as lower immunogenicity and easy production, handling, and storage.

Conclusion: Compared with traditional therapies, MSC and secretome treatment can directly improve TBI-induced pathological changes and promote recovery of neurological function. MSCs and their secretome hold great promise to bridge this gap in translation for TBI. Further clinical trials are needed to confirm its efficacy and safety.

Keywords: Mesenchymal stem cell, Neuroprotection, Secretome, Traumatic brain injury

INTRODUCTION

More than 27 million people were diagnosed with and treated for traumatic brain injury (TBI) in 2016, with an age-adjusted incidence of 369/100,000 persons around the world, according to the largest study to date estimating the global incidence of TBI. More than 55 million people around the world are thought to be living with a TBI, according to this study.[ 19 ] This represents roughly 0.7% of the global population. Low- and middle-income countries (e.g., Indonesia) have nearly 3 times as many TBI cases as high-income countries due to a higher prevalence of risk factors for TBI causes (e.g., motor vehicle crashes and falls from height) and differences in health-care systems that allow patients to seek medical care and address associated health effects. The estimated cost of non-fatal TBI-related health care in the United States in 2016 was $40.6 billion, while global hospitalization expenses for severe TBI ranged between $2,130 and $401,008. Developing countries also face these problems.[ 18 ]

Multiple mechanisms, including excitotoxicity, mitochondrial dysfunction, oxidative stress, lipid peroxidation, neuroinflammation, axon degeneration, and apoptotic cell death, contribute to secondary injuries. Recent advances in neuroprotection have acknowledged this intricate structure and interplay, placing greater emphasis on therapeutic measures that encourage the recovery and optimal performance of nonneuronal cells as well as more directly obstructing neuronal cell death pathways . Moleac901 promotes neurogenesis.[ 19 ] Previous studies showed the role of erythropoietin, high mobility group box 1, in potential treatment in TBI.[ 19 , 23 ] Mild hypothermia therapy also affects matrix metalloproteinase 9 (MMP-9) protein level, MMP-9 messenger RNA (mRNA), 1562 C/T Polymorphism, and Marshall computed tomography (CT) score in high-risk TBI.[ 12 , 13 , 16 ] Mesenchymal stem cells (MSCs) also show tremendous promise in terms of neuroprotection in experimental TBI. Not only MSCs but also their released bioactive substances, known as the secretome, can provide immunomodulation for tissue regeneration and neurological recovery after TBI.[ 23 ] Some previous research studied the potential therapeutic rat model of TBI. The model of rat TBI was also reported with a modification of the Marmarou model.[ 15 ] Caffeic acid phenethyl ester can reduce brain edema in TBI subjects.[ 14 , 16 ]

In 2016, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy defined MSCs as meeting three criteria: (1) In vitro multipotent differentiation potential to osteoblasts, adipocytes, and chondroblasts; (2) must express specific surface markers of CD105, CD73, and CD90, and lack expression of CD45, CD34 or CD14 or CD11b, CD79 alpha or CD19, and human leukocyte antigen - DR(HLA-DR); and (3) must be plastic-adherent when maintained in standard culture conditions. MSCs have been extensively investigated in the treatment of numerous human diseases, including type 1 diabetes, neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, spinal cord injuries, and tumors. Constant interaction between MSCs and the immune system is essential for maintaining tissue homeostasis and regulating inflammatory responses. MSCs can inhibit CD4+ (helper) and CD8+ (cytotoxic) T cells, affect B-cell functions through cell-to-cell contact, suppress the proliferation and cytotoxicity of natural killer (NK) cells, and increase regulatory T-cell (Treg) generation in vitro and in vivo through cell communication and soluble factors.[ 7 ] Many studies indicate that many of the therapeutic effects of MSCs may be due to the paracrine substances secreted by extracellular vesicles rather than cellular engraftment and response to the site of injury. Exosomes derived from mesenchymal stem cells have been found to be effective in a growing number of animal models for the treatment of liver fibrosis, liver injury, hypoxic pulmonary hypertension, acute lung injury, acute renal injury, and cardiovascular diseases. This hypothesis is supported by preclinical studies demonstrating comparable or even enhanced organ function following infusion of mesenchymal stem cell conditioned medium(MSC-CM) as opposed to MSC transplantation. Furthermore, it has been demonstrated that MSC-derived exosomes are as effective as MSCs in enhancing functional outcomes, further demonstrating the significance of the secretome in promoting stroke repair. In TBI, exosomes from bone marrow mesenchymal stem cells (BMMSCs) could reduce neuroinflammation by regulating the phenotypes of microglia and aiding in the healing of nerve damage.

MATERIALS AND METHODS

Literature search

This methods section provides a structured approach for conducting a thorough and systematic review of the existing literature on MSC secretome in TBI, ensuring transparency, reproducibility, and rigor in the evaluation of preclinical and clinical evidence.

A comprehensive and systematic literature search was conducted to identify relevant studies on the preclinical and clinical trials of mesenchymal stem cell (MSC) secretome in the context of TBI. The search was performed using the following electronic databases up to June 2024: PubMed/MEDLINE, EMBASE, Web of Science, Scopus, and Cochrane Library.

The search strategy incorporated a combination of keywords and Medical Subject Headings terms related to MSC secretome and TBI. The primary search terms included: “Mesenchymal Stem Cells,” “MSC Secretome,” Traumatic Brain Injury,” “Preclinical Trials,” “Clinical Trials,” “Therapeutic Efficacy,” and “Neuroprotection.” Boolean operators (AND, OR) were used to refine the search. In addition, reference lists of identified articles and relevant reviews were manually searched to capture any studies not retrieved through the database search.

Study selection

The study inclusion and exclusion criteria were as follows:

Inclusion criteria

Study Type: Both preclinical (in vitro and in vivo) and clinical studies evaluating the therapeutic potential of MSC secretome in TBI

Data extraction

A standardized data extraction form was developed to collect pertinent information from each included study. The following data were extracted: general information, study design, intervention details, outcomes measured, and results.

Data synthesis and quality assessment

The extracted data were synthesized through a qualitative and quantitative approach to evaluate the therapeutic efficacy of MSC secretome in TBI. Preclinical and clinical studies were categorized based on their study design, intervention type, and outcome measures. The synthesis focused on neuroprotective effects, functional recovery, molecular mechanisms, safety and adverse events, and efficacy in clinical trials. A narrative synthesis was conducted to integrate findings across studies.

Institutional Review Board (IRB)

This article has been exempted from IRB review ref. No 9886/UN4.6.8/PJ.00.01/2024 from Faculty of Medicine, Hasanuddin University.

RESULTS

Based on the systematic multi-database analysis, clinical trials of stem cells have been performed all around the world, with a total of 131 consisting of 101 observational and 30 interventional studies performed predominantly in the USA and China. In conclusion, these results suggested that only a small number of clinical trials focused on the transplantation of stem cells into patients with a relatively restricted range of diagnoses. This study was also supported by other reviews in which only five in vitro studies and nine in vivo studies until 2022 have been published to support data on the use of MSCs secretome in TBI.

Several clinical studies have evaluated the safety and efficacy of mesenchymal stem cell (MSC) therapy for patients with TBI, demonstrating potential benefits in neurological function, motor recovery, and inflammation reduction [ Figure 1 ].

Figure 1:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart. n: Number of articles.

Motor function improvement in chronic TBI

The Stem Cell Therapy for Traumatic Brain Injury( STEMTRA) trial (NCT02416492, Phase 2, n = 63) assessed the efficacy of allogeneic SB623 cell transplantation in chronic TBI patients with motor deficits. The study found a significant improvement in Fugl-Meyer Motor Scale scores at 24 weeks (P = 0.040), with no dose-limiting toxicities or deaths. However, secondary outcomes did not reach statistical significance.

Safety and inflammatory response in acute TBI

A Phase 1/2 study (NCT01575470, n = 25) on autologous bone marrow mononuclear cell (BMMNC) transplantation in severe TBI patients within 36 h post-injury reported no severe adverse events. In addition, structural preservation of brain tissue and a significant reduction in inflammatory markers (Interleukin-1beta [IL-1β], interferon-gamma [IFN-γ], and tumor necrosis factor-alpha [TNF-α]) were observed, suggesting a neuroprotective role of stem cell therapy.

Neurological and functional recovery with umbilical cord MSCs

A Phase 2 study (n = 40) investigating umbilical cord mesenchymal stem cell (UCMSC) transplantation in TBI patients with sequelae found significant improvements in neurological function and self-care ability based on Fugl-Meyer Assessments and Functional Independence Measures at 6 months post-transplantation.

Reduction in intracranial pressure (ICP) and neurointensive care duration

A Phase 1 study (n = 29) on autologous BMMNC therapy in pediatric TBI patients reported a significant reduction in Pediatric Intensity Level of Therapy scores within 24 h post-treatment, persisting for 1 week (P < 0.05). In addition, the therapy reduced the need for prolonged neurointensive care, as reflected in a shorter duration of ICP monitoring compared to controls (8.2 ± 1.3 vs. 15.6 ± 3.5 days, P = 0.03).

Brain function and motor recovery in subacute TBI

A Phase 1 study (n = 97) evaluating autologous BMMSC therapy through lumbar puncture reported functional improvements in 39.2% (38/97) of patients (P = 0.007). Among patients in a persistent vegetative state, 45.8% (11/24) showed increased consciousness (P = 0.024), while 37.0% (27/73) with motor disorders exhibited motor function recovery (P = 0.025). The age of patients and time from injury to therapy significantly influenced outcomes (P < 0.05), whereas the number of cell injections did not correlate with improvements (P > 0.05).

Safety and feasibility in pediatric TBI

A Phase 1 study (NCT00254722, n = 10) confirmed the safety and feasibility of autologous bone marrow progenitor cell infusion in pediatric TBI patients within 24 h of injury. The study reported no severe adverse effects and suggested potential functional improvements.

Long-term safety and efficacy in chronic TBI

An open-label Phase 1 study (NCT02028104, n = 50) on autologous BMMNC therapy in chronic TBI patients (1–65 years) demonstrated long-term safety and efficacy, with reported improvements in common TBI symptoms over follow-up periods.

Preclinical studies on MSC secretome in TBI

Preclinical research has further highlighted the therapeutic potential of MSC-derived secretome in modulating inflammation, reducing oxidative stress, and promoting neuroprotection in TBI models.

In vitro studies

Human adipose-derived MSCs (ASC) increased wound closure and reduced oxidative stress in injured astrocytes (Torrente et al., 2014)[ 24 ]

In vivo studies

Intravenous infusion of ASC secretome improved sensorimotor and cognitive functions, decreased neuroinflammation, and reduced apoptosis in a TBI rat model (Xu et al., 2020)[ 28 ]

MSC therapy, including bone marrow-derived and umbilical cord-derived stem cells, has demonstrated safety and potential efficacy in improving neurological function, motor recovery, and inflammatory regulation in both clinical and preclinical TBI studies. While early-phase clinical trials suggest promising benefits, further large-scale randomized controlled trials are needed to confirm the long-term therapeutic effects and optimize treatment protocols.

DISCUSSION

Molecular pathophysiology of TBI

Brain trauma can be categorized into primary and secondary brain injuries, which encompass the injury process. The occurrence of primary brain damage is attributed to the direct application of force on nerve cells, which might manifest as contact or inertial forces. These pathways ultimately result in neuronal apoptosis, synaptic plasticity, tissue injury, and cerebral shrinkage.[ 26 ] Secondary injury mechanisms are also triggered immediately after the traumatic incident and continue as a sequence. Several biochemical changes contribute to secondary injury, including disruptions in cellular calcium balance, glutamate excitotoxicity, mitochondrial dysfunction, heightened production of free radicals, inflammation, increased lipid peroxidation, apoptosis, diffuse axonal injury, and breakdown of the blood-brain barrier (BBB). This inflammation has been implicated in both the initial and long-term aspects of neuropathology resulting from TBI.

Excitotoxicity is the main cause of various events that occur after TBI. Glutamate levels have been found to be at their peak immediately following TBI and remain elevated for a period of 24–48 h. This is mainly attributed to the mechanical disruption of the BBB. Some studies correlate the excessive glutamate levels linked to cerebral ischemia, seizures, and increased ICP.[ 29 ] Elevated levels of calcium within cells trigger the activation of many destructive enzymes, such as phospholipases that harm cell and mitochondrial membranes, proteases that damage the cell’s cytoskeleton, and endonucleases that induce deoxyribonucleic acid (DNA) breakage. This leads to both apoptosis and necrosis.

Inflammation is a protective response that occurs when tissue homeostasis is disrupted by pathogens, physical agents, toxins, vascular changes, tissue necrosis, or immunological reactions. The immune cells present in the brain parenchyma, both those that originate from outside the brain and those that reside within it, release various substances that promote inflammation. These substances include damage-associated molecular patterns( DAMPs), cytokines, chemokines, reactive oxygen species(ROS), prostaglandins, and complement factors. Several studies have documented an increase in the expression of IL-1β, TNF-α, IL-6, C-C motif chemokine ligand 2(CCL2), CCL3, C-X-C motif chemokine ligand (CXCL1), CXCL2, CXCL8/IL-8, CXCL10, C-C chemokine receptor (CCR)2, CCR5, C-X-C chemokine receptor (CXCR) 4, and CX3CR1 within 6 h of TBI.[ 25 ] The post-TBI triggers the release of inflammatory mediators that not only modify the resident cells of the central nervous system but also attract peripheral cells to enter the brain. Signals from the surrounding tissue microenvironment influence the polarization of these immune cells toward pro-inflammatory or anti-inflammatory phenotypes. After experiencing a TBI, astrocytes rapidly become active and undergo substantial structural alterations, including the shortening of their processes and swelling of their cell bodies, resulting in a hypertrophic form.[ 1 ]

Astrocytes, when activated, perform the functions of engulfing debris and producing various substances such as cytokines, chemokines, and inflammatory mediators such as TNF-α, cyclooxygenase-2, and MMP-9 to support the ongoing inflammatory process. The activation of microglia during a TBI leads to an increase in the inflammatory response since it triggers the production and release of TNF-α and interleukins such as IL-1β and IL-6. Cytokine interactions lead to the movement of monocytes toward the location of the injury. At the site of the injury, cytokines, including IFN-γ and monocyte chemoattractant protein-1, continue to stimulate the macrophages, causing them to gather at the site of inflammation.[ 11 ] The macrophages further contribute to the worsening of the inflammatory process by continuously producing TNF-α and IL-1 [ Figure 2 ].

Figure 2:

Pathophysiology of traumatic brain injury. APC: Antigen-presenting cell, ATP: Adenosine triphosphate, BBB: Blood-brain barrier, CREB: cAMP response element-binding protein, NMDA: N-methyl-D-aspartate, NOS: Nitric oxide synthase, OH: Hydroxyl radical, PKC: Protein kinase C, PLC: Phospholipase C, PN: Peroxynitrite, ROS: Reactive oxygen species, SDF: Stromal cell-derived factor, TNF: Tumor necrosis factor.

Biomarkers following TBI

Biomarkers associated with TBI are commonly quantified in bodily fluids. The majority of the data currently accessible were acquired through measures conducted in cerebrospinal fluid (CSF), blood (serum or plasma), or saliva. The glial protein S100B and neuron-specific enolase (NSE) were formerly thought to have a direct correlation with the severity of brain damage following an injury. The presence of markers in blood or other biological fluids may occur through BBB disruption or release, regardless of BBB integrity, or through passage through the recently found glymphatic system. The integrity of the BBB can be evaluated by measuring the ratio of albumin levels in the CSF to those in the serum. This assessment can help determine if the BBB has been compromised due to trauma or other pathological factors. In cases of severe TBI, the disruption of the BBB leads to an increase in the ratio of CSF to serum albumin. In cases of mild TBI, the ratio of CSF to serum albumin remains mostly within the normal range. Indicators of sudden damage to astroglial cells consist of increased levels of S100B and elevated levels of glial fibrillary acidic protein(GFAP), which can be identified in both CSF and peripheral blood.[ 5 ]

NSE, α-II spectrin, and ubiquitin carboxyl-terminal hydrolase L1(UCH_L1) are biomarkers that indicate acute neuronal injury in TBI. Elevated levels of NSE were observed in both the CSF in the brain’s ventricles and the blood serum in investigations of severe TBI. The extent of this elevation was directly related to greater mortality rates and more severe scores on the Glasgow Coma Scale (GCS) for both adults and children. The increased levels of spectrin breakdown products and UCH-L1, along with GFAP, have been found to be directly connected to the severity of trauma. These biomarkers also enhance the predicted accuracy of the IMPACT outcome calculator for patients with severe TBI.[ 6 ] Fluid indicators of acute axonal damage comprise tau proteins, neurofilament light peptide, and phosphorylated neurofilament heavy peptide.[ 13 , 18 ]

Role of MSCs and secretome in TBI

The medical community faces a significant problem in optimizing the therapy and prevention of subsequent damage after TBI. Animal investigations of brain vascular injuries have demonstrated that the administration of molecular agents that enhance the expression of transcription factors responsible for regulating cytoprotective proteins can provide neuroprotection and reduce the breakdown of the BBB.

The process of neurogenesis in the brain of a young adult can be broken down into a series of distinct developmental steps, each of which can be studied separately. These steps include the proliferation of precursor cells, the survival of newly born cells, their migration, and their differentiation into mature, functional neurons. Precursor cells can be stem cells, which have a slow-dividing cell cycle, long-term self-renewal potential, and multipotentiality, or progenitors, which have an increased rate of turnover and diminished self-renewal capabilities.

Animal trial of MSCs in TBI

According to a collection of laboratory studies conducted on TBI, the secretome was found to enhance the healing of wounds by promoting cell survival and growth, reversing structural changes, and increasing the movement and alignment of cells. These effects were observed to be dependent on the dosage of the secretome. The majority of the studies have demonstrated a significant improvement in mitochondrial function. This is achieved through the decrease in harmful free radicals (O₂⁻), the maintenance of the mitochondrial membrane potential, and the increase in the production of mitochondrial antioxidant enzymes (superoxide dismutase 2(SOD2), glutathione peroxidase 1(GPX-1), and catalase). In addition, there is a reduction in oxidative stress, decreased DNA damage and nuclear fragmentation, and modulation of inflammatory cytokines. Specifically, there is a decrease in the expression of IL-6, TNF-α, and granulocyte-macrophage colony-stimulating factor(GM-CSF) and an increase in the expression of IL-2 and IL-8. These findings indicate that the secretome treatment has a targeted effect in reducing apoptosis.

Clinical trial of stem cell and cell therapy in TBI

Several pioneer studies have shown the harmlessness and usefulness of cell therapy in treating pathological TBI. Based on an interim analysis of the STEMTRA trial, which included 63 TBI patients given allogeneic modified bone marrow-derived MSCs, they showed SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls.[ 9 ] Sharma et al. studied to study the effects of intrathecal transplantation of autologous BMMNCs in 50 patients with chronic TBI. The results showed that 92% of patients experienced improvements in various symptoms and functional abilities. Factors such as age, severity of injury, and time since injury were found to affect the outcome of the transplantation. The study suggests that cell transplantation, combined with neurorehabilitation, can enhance functional recovery and improve the quality of life in patients with chronic TBI, particularly in younger patients with milder injuries.[ 20 ]

Wang et al., in 2013, investigated the effects of UCMSC transplantation on patients with sequelae of TBI. The results showed that stem cell transplantation significantly improved neurological function, including upper and lower extremity motor function, sensation, balance, self-care, mobility, communication, and sphincter control. These findings suggest that stem cell transplantation with UCMSCs may be a safe and effective treatment for TBI sequelae. The study also highlighted the potential mechanisms through which stem cell transplantation may improve neurological function, including cell replacement, trophic support, and stimulation of endogenous neural repair and regeneration.[ 27 ] Another study included a total of 97 patients with severe traumatic brain injury (sTBI) (24 with persistent vegetative state and 73 with disturbance in motor activity) who received autologous BMMSC therapy. The study showed that 38/97 patients (39.2%) improved in the function of the brain after transplant; 11/24 patients (45.8%) with persistent vegetative state showed improvements in consciousness; and 20/73 patients (37.0%) with a motor disorder showed improvements in motor functions.[ 22 ]

Cox et al., in 2017, studied 25 patients with sTBI given the low dose, medium dose, and high dose of autologous BMMNCs to receive target doses of 6 × 10⁶ BMMNC/kg, 9 × 10⁶ BMMNC/kg, and 12 × 10⁶ BMMNC/kg, respectively, for every group. Functional and neurocognitive outcomes were measured and correlated with imaging data. They concluded that treatment of BMMNC was safe and appeared to preserve critical regions of interest that correlated with functional outcomes.[ 4 ] In a study regarding the use of BMMNC in pediatric patients, they studied 10 sTBI children treated with 6 × 10⁶ autologous BMMNCs/kg body weight delivered intravenously within 48 h after TBI. The study concluded that GCS in 6 months showed 70% with good outcomes and 30% with moderate to severe disability. They also concluded the use of BMMNC in children is feasible and safe.[ 3 ] Another study conducted in the pediatric population was conducted in 2015 by Liao et al. They included 29 sTBI patients which treated with intravenous autologous BMMNCs in 19 patients. The study showed that intravenous autologous BMMNC therapy was associated with lower treatment intensity required to manage ICP, associated severity of organ injury, and duration of neurointensive care following severe TBI.[ 10 ] All studies are concluded in Table 1 .

Table 1:

Clinical study for MSC in TBI.

Preclinical study of the role of the secretome in TBI

In general, the secretome is generated using a variety of protocols. The most frequently employed MSC source is adipose tissue (ASC). Table 2 summarizes the findings of in vitro TBI studies that investigate the effects of the secretome and potential mechanisms of action. The same research group conducts the majority of studies and utilizes the human astrocyte-cell line (T98G) that has been exposed to scratch injury (which simulates mechanical injury) in conjunction with glucose deprivation (which induces metabolic impairment). The reduction of free radicals (O₂⁻) has been demonstrated to be a distinct benefit to mitochondrial function among secretome-induced mechanisms of action.[ 24 ] The application of ASC-derived secretome treatment to scratch-injured neurons resulted in a reduction in cell mortality, diminished mitochondrial dysfunction, and a decrease in the expression of the pro-inflammatory cytokine IL-1β.[ 8 ]

Table 2:

Preclinical study of MSC secretome.

Additional mechanisms of action included the decrease in the expression of IL-6, TNF-α, and GM-CSF, as well as the increase in the expression of IL-2 and IL-8 and the modulation of inflammatory cytokines. Intriguingly, the secretome treatment resulted in an increase in the production of Ngb in astrocytes. The secretome’s protective effects on mitochondrial injury in astrocytes were significantly diminished when Ngb was suppressed by small interfering RNA(siRNA).[ 2 ] In rodent models of TBI, the secretome enhances functional recovery and improves neurological outcomes. Enhancements in cognitive function, including spatial learning and memory, and sensorimotor deficits. Secretome also possesses potent immunomodulatory properties, which result in a reduction in the expression of pro-inflammatory cytokines (e.g., IL-6 and TNF-α) and a concurrent increase in anti-inflammatory cytokines (e.g., Transforming growth factor-beta) in injured brain tissue. This shift in microglia/macrophage activation toward protective phenotypes is characterized by a decrease in Iba₁ +/NOS₂ + and an increase in Iba₁ +/Arg₁ + cells.[ 28 ]

The efficacy of MSC or secretome in TBI in geriatric animals is inadequately investigated, with only a small amount of studies available. Tajiri et al. demonstrated the efficacy of intravenous ASCs transplantation or their secretome in young TBI rats (6 months of age). However, these interventions had diminished or no benefit in aged TBI rats (20 months of age). In particular, secretome treatment enhanced neurological recovery and diminished anatomical injury in young TBI rodents; however, it was ineffective in aged TBI rats. As an aside, the treatment with the cellular counterpart ASC resulted in an improvement in sensorimotor and cognitive functions, as well as reduced anatomical damage, in young rats. Conversely, it partially improved cognitive function recovery and anatomical damage in aged TBI rats, suggesting that the responsiveness to MSC or secretome treatment is age-dependent. The observation that secretome treatment is protective in young TBI animals but not in aged TBI animals may be attributed to the aged brain’s diminished capacity to respond to trophic/regenerative stimuli and/or a dysregulated immune response in the aged brain that is less responsive to secretome immunomodulatory activity.[ 21 ]

The phenotypes and functions of immune cells have been identified as potently regulated by factors released by MSCs. Each time a particular factor is inhibited, the efficacy of MSCs is diminished, suggesting that this factor plays a critical role in comparison to the others. However, the majority of these observations have been made using in vitro systems that are overly simplified, as they only permit binary interactions between MSCs and immune cells. There is a possibility that a single compound will not be sufficient to accomplish protection in vivo, and the synergistic effects of multiple mediators will be required. This translation gap for complex neurological disorders, such as TBI, is of tremendous potential to be bridged by MSCs and their secretome. Nevertheless, the present challenge is to identify the optimal combination of bioactive factors released by MSCs that will enhance functional recovery and provide sustained neuroprotection.[ 17 , 21 ]

Future consideration

Significant data from preclinical research demonstrate that the secretome produced from mesenchymal stem cells (MSCs) is a promising biotherapeutic product that may effectively alleviate the pathological alterations associated with TBI. Although the secretome has several therapeutic advantages in treating TBI, it is important to acknowledge and tackle the limitations associated with its use in order to ensure its wider acceptance in clinical settings. Preclinical experiments have demonstrated the safety of secretome for the treatment of TBI. However, to achieve the creation of clinically quality secretome, it is crucial to standardize the manufacturing process. This is because variations in growth conditions and the source of MSCs might result in varying quantities of these secreted proteins. Similarly, it is necessary to standardize the characterization procedure to determine the precise quantities of different bioactive compounds. This will enable the selection of a suitable therapeutic dosage for administration. In addition to the challenges in production, it is crucial to take into account the mechanism of action of secretome for its successful use in regenerative medicine.

CONCLUSION

MSCs have proven thorough examination in both preclinical and clinical studies. Multiple studies provide evidence supporting the safety and little danger of using MSCs as a cell-based therapy for treating TBI. The therapeutic effectiveness of secretome, independent of the cells, indicates that the paracrine mechanism, rather than differentiation, is one of the primary ways in which MSCs provide therapeutic advantages. Utilizing the released substances of MSCs for TBI therapy might have significant advantages in improving the physiological implications of neurological impairment in TBI.

The secretome provides therapeutic benefits through several pathways, including angiogenesis, neurogenesis, anti-inflammatory responses, and immunomodulatory properties. While there has been some progress in using secretome as a therapeutic approach for TBI, further work is required to address the obstacles identified in this study to apply these therapeutic strategies in a clinical setting successfully.

Ethical approval:

The Institutional Review Board approval is not required.

Declaration of patient consent:

Patient’s consent was not required as there are no patients in this study.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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