Exosome-Facilitated Spinal Cord Injury Repair: Advancing a Therapeutic Modality

Exosome-Facilitated Spinal Cord Injury Repair: Advancing a Therapeutic Modality

A spinal cord injury (SCI) is a serious condition that affects the central nervous system, leading to loss of movement, sensation, and bodily functions below the site of the injury. SCI is not only life-changing for those affected but also presents a significant burden on healthcare systems worldwide. Each year, thousands of people experience SCI due to accidents, falls, or medical conditions, and unfortunately, there is currently no way to fully restore lost function.

After an SCI occurs, the damage progresses in two stages: primary and secondary injury. The primary injury happens immediately upon impact, causing direct harm to the spinal cord. This is followed by secondary injury, a complex process where inflammation, cell death, and scar formation make it even more difficult for the spinal cord to heal. 

In this review, Yu et al. review how exosomes are prepared, their functions, administration routes, and their role in repairing SCI, including their effectiveness alone and in combination with other treatments.

Understanding Exosomes: Functions, Benefits, and Applications

Exosomes are tiny particles that cells release into their surroundings. These microscopic vesicles, which range in size from 30 to 150 nanometers, help cells communicate by carrying proteins, genetic material, and other molecules from one cell to another. Exosomes play a key role in many biological processes, including immune responses, tissue repair, and even disease progression.

According to the authors, scientists have recently begun exploring the potential of exosomes in medicine, particularly for treating spinal cord injuries. Since exosomes are naturally produced by cells and can travel throughout the body, they have the potential to serve as powerful tools for healing damaged tissues, reducing inflammation, and encouraging nerve regeneration.

How Exosomes Can Help Repair SCI

Promoting Nerve Regeneration

One of the most notable challenges in SCI recovery is nerve regeneration. Nerve cells, or neurons, do not repair themselves easily after damage. However, research has shown that exosomes may help stimulate this process. Certain types of exosomes have been found to contain molecules that encourage nerve cell growth and survival. By delivering these molecules to injured areas, exosomes may promote the repair of damaged nerves and improve functional recovery.

Reducing Inflammation

Inflammation is a major contributor to secondary injury after SCI. When the spinal cord is damaged, immune cells rush to the site, releasing chemicals that cause swelling and further harm to nerve cells. Exosomes have been shown to help regulate the immune response by reducing inflammation and preventing excessive damage. By controlling the body’s inflammatory reaction, exosomes may create a more favorable environment for healing.

Protecting Against Cell Death

After SCI, many nerve cells die due to stress and lack of oxygen. Exosomes may offer protection by delivering molecules that help cells survive. Some exosomes have been found to block pathways that lead to cell death, allowing more neurons to stay alive and functional. This protective effect could be crucial in limiting the long-term effects of SCI.

Encouraging Blood Vessel Growth

Blood flow is essential for delivering oxygen and nutrients to the spinal cord. After an SCI, blood vessels in the area may be damaged, further reducing the chances of recovery. Exosomes have been found to support the growth of new blood vessels, improving circulation to injured areas. This process, known as angiogenesis, can help supply the spinal cord with the nutrients it needs to repair itself.

Combating Oxidative Stress

Oxidative stress is another factor that worsens spinal cord injuries. It occurs when harmful molecules called free radicals accumulate and damage cells. Exosomes contain antioxidants that can neutralize these harmful molecules, protecting nerve cells from additional damage. By reducing oxidative stress, exosomes may help preserve spinal cord function and promote healing.

Using Exosomes for SCI Treatment

Direct Injection

One way to use exosomes for SCI treatment is by injecting them directly into the injured area. This method allows exosomes to reach damaged nerve cells quickly and begin their repair work. However, one challenge with this approach is that exosomes may not stay in place long enough to have a lasting effect. Scientists are working on ways to improve the stability and effectiveness of direct injections.

Intravenous Delivery

Another method is intravenous (IV) delivery, where exosomes are injected into the bloodstream. This allows them to travel throughout the body and potentially reach the spinal cord. While IV delivery is less invasive than direct injection, some exosomes may be filtered out by organs like the liver before they reach the injury site. Researchers are exploring ways to improve targeting so that more exosomes reach the spinal cord.

Exosomes Combined with Biomaterials

Scientists are also investigating the use of biomaterials, such as hydrogels, to help exosomes stay at the injury site longer. Hydrogels are soft, water-based materials that can hold exosomes in place, slowly releasing them over time. This controlled release may enhance the effectiveness of exosome therapy and provide a more sustained healing effect.

The Future of Exosome Therapy for Spinal Cord Injury

According to Yu et al. emerging research suggests that exosomes could play a crucial role in promoting healing and improving recovery. 

While there are still many questions to answer and challenges to overcome, the authors conclude the potential of exosomes in medicine is undeniable. With continued research and development, exosome therapy could one day provide a groundbreaking solution for spinal cord injury patients, helping them regain function and improve their quality of life.

Source: Yu, T., Yang, LL., Zhou, Y. et al. Exosome-mediated repair of spinal cord injury: a promising therapeutic strategy. Stem Cell Res Ther 15, 6 (2024). https://doi.org/10.1186/s13287-023-03614-y

CELLTOP Clinical Trial: Phase 1 Findings on Adipose-Derived Stem Cell Therapy for Spinal Cord Injury Paralysis

CELLTOP Clinical Trial: Phase 1 Findings on Adipose-Derived Stem Cell Therapy for Spinal Cord Injury Paralysis

Spinal cord injuries (SCI) are life-altering conditions with limited treatment options. While rehabilitation and medical management can provide some improvements, regenerative medicine is emerging as a promising alternative. The CELLTOP study, an on-going multidisciplinary phase 1 study conducted at the Mayo Clinic, is investigating the safety and efficacy of adipose tissue–derived mesenchymal stem cells (AD-MSCs) to aid in spinal cord recovery. 

In this initial report, Bydon et al. describe the outcome of the study’s first treated patient – a 53-year-old survivor of a surfing accident who sustained a high cervical American Spinal Injury Association Impairment Scale grade A SCI with subsequent neurologic improvement that plateaued within 6 months following injury.

The CELLTOP Trial Stem Cell Treatment Process 

Nine months after his injury, the patient enrolled in the CELLTOP study. An abdominal fat tissue sample was collected, and stem cells were isolated, expanded, and preserved. Eleven months after the injury, the patient received an injection of 100 million AD-MSCs through a lumbar puncture at the L3-4 level.

Safety and Tolerability: Minimal Side Effects Observed in Trial

According to the authors, the procedure was well tolerated. The only reported side effect was a mild to moderate headache on the second day, which resolved with over-the-counter medication. No severe adverse effects were observed during the 18-month follow-up.

Observed Neurological Improvements 

Following the stem cell injection, the patient showed notable improvements in motor and sensory function over 18 months, including:

  • Motor Function: The patient’s upper limb motor scores improved from 35 at baseline to 44 at 18 months. Lower limb motor scores increased from 36 to 49. These improvements were observed in both sides of the body.
  • Sensory Function: Sensation, measured through pinprick and light touch scores, nearly doubled. The pinprick score increased from 45 to 95, and the light touch score improved from 54 to 96.
  • Upper Extremity Capabilities: The patient’s ability to use his arms and hands improved significantly, particularly in tasks requiring pulling, pushing, and finger dexterity.
  • Quality of Life: The patient’s physical and mental health scores improved, as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire.

Observed Improvements in Physical Therapy Performance 

Over the 18-month follow-up, the patient also demonstrated significant progress in mobility and strength, including:

  • His walking speed improved from 0.17 m/s to 0.43 m/s.
  • Walking distance increased from 635 feet in 12.8 minutes to 2200 feet in 34 minutes.
  • Shoulder flexibility improved, with greater range of motion in both arms.
  • Grip strength and hand dexterity showed notable gains.

How Stem Cells Aid in Spinal Cord Repair

SCI leads to significant nerve damage and scarring that inhibit natural healing. Stem cells offer potential benefits by:

  • Reducing Inflammation: AD-MSCs have anti-inflammatory properties that may create a more favorable environment for nerve regeneration.
  • Promoting Tissue Repair: These cells can support the growth of new nerve cells and blood vessels, enhancing recovery.
  • Enhancing Neuroprotection: Stem cells may help preserve existing nerve function and prevent further deterioration.

Future Prospects of Regenerative Medicine for SCI 

While this case study presents promising results, further research is necessary. The CELLTOP study continues to evaluate the effectiveness of stem cell therapy in more patients. Future related studies will explore optimal dosing, timing, and potential combination therapies to enhance recovery further.

Based on these initial results, the authors conclude that regenerative medicine -particularly stem cell therapy – holds significant promise for treating SCI. The first patient in the CELLTOP study demonstrated meaningful neurological improvements, suggesting that AD-MSC therapy could offer new hope for those with SCI. Continued research and clinical trials will determine whether this treatment can become a standard option for spinal cord injury recovery.

Source: Bydon M, Dietz AB, Goncalves S, Moinuddin FM, Alvi MA, Goyal A, Yolcu Y, Hunt CL, Garlanger KL, Del Fabro AS, Reeves RK, Terzic A, Windebank AJ, Qu W. CELLTOP Clinical Trial: First Report From a Phase 1 Trial of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells in the Treatment of Paralysis Due to Traumatic Spinal Cord Injury. Mayo Clin Proc. 2020 Feb;95(2):406-414. doi: 10.1016/j.mayocp.2019.10.008. Epub 2019 Nov 27. PMID: 31785831.

Administration of Adipose-Derived Mesenchymal Stem Cells via Intrathecal Injection for Traumatic Spinal Cord Injury

Administration of Adipose-Derived Mesenchymal Stem Cells via Intrathecal Injection for Traumatic Spinal Cord Injury

With over 290,000 people in the United States living with SCI and with roughly 17,000 new cases each year, spinal cord injury (SCI) is a serious condition that significantly impacts the lives of those affected. 

Considering the complexity associated with SCI, current treatments for SCI continue to focus mainly on managing symptoms and providing physical rehabilitation. However, recently there has been growing interest in exploring the potential of regenerative medicine, particularly stem cell therapy, for treatment of SCI.

Bydon et al.’s Phase I clinical trial explored the safety of injecting autologous adipose-derived mesenchymal stem cells (AD-MSCs) into the spinal fluid of patients with traumatic spinal cord injury (SCI). 

The study successfully manufactured and administered the stem cells to all patients without any serious adverse events (AEs). Although some non-serious AEs, including headache and musculoskeletal pain, were observed, none of the patients were excluded from the study as a result. 

At the conclusion of this study, the authors found that several participants showed improvements in sensory and motor functions, as assessed by the American Spinal Injury Association (AIS) impairment scale.

Previous research has indicated that mesenchymal stem cells (MSCs) might aid in neurogenesis, angiogenesis, immune regulation, and neuronal plasticity. AD-MSCs, in particular, are advantageous due to their ability to regenerate nerves and blood vessels, their ease of extraction, and availability. 

This study’s findings align with earlier studies, which also reported no serious AEs from intrathecal AD-MSC injections in SCI patients. Similar safety profiles were observed in studies involving other neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and multiple sclerosis.

Bydon et al.’s reported changes in MRI scans following the stem cell injections as part of this study. Previous studies have reported mixed conclusions on whether these changes are linked to neurological decline. Some suggest that these MRI findings could be due to inflammation from the stem cell treatment, potentially leading to nerve root compression. However, in this study, the authors found that these MRI changes did not correlate with neurological deterioration, indicating that they might be benign reactions.

While some patients showed improvements in their AIS grades, the authors caution that these findings should be carefully interpreted due to the limitations associated with this Phase I trial, including the lack of a control group. 

Bydon et al. call for future larger-scale, randomized controlled trials to conclusively determine the benefits of AD-MSC injections. Additionally, they recommend expanding the study to include a broader range of cytokines and immunomodulatory markers to provide a deeper understanding of the stem cells’ mechanisms.

The authors conclude that this trial demonstrated the safety of intrathecal AD-MSC injections in SCI patients, with no serious AEs reported. Seven out of ten patients showed improvements in their AIS grades. These results encourage further research to evaluate the impact of AD-MSCs on neurological outcomes and to explore their potential in aiding late-stage recovery in SCI patients.

Source: Bydon M, Qu W, Moinuddin FM, Hunt CL, Garlanger KL, Reeves RK, Windebank AJ, Zhao KD, Jarrah R, Trammell BC, El Sammak S, Michalopoulos GD, Katsos K, Graepel SP, Seidel-Miller KL, Beck LA, Laughlin RS, Dietz AB. Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial. Nat Commun. 2024 Apr 1;15(1):2201. doi: 10.1038/s41467-024-46259-y. Erratum in: Nat Commun. 2024 Jun 5;15(1):4799. doi: 10.1038/s41467-024-48979-7. PMID: 38561341; PMCID: PMC10984970.

Mesenchymal Stem Cells for Managing Spinal Cord Injuries

Mesenchymal Stem Cells for Managing Spinal Cord Injuries

Nerve damage resulting from spinal cord injury (SCI) often leads to temporary or permanent loss of function and contributes to poor quality of life. Most common among males below 30 years of age, SCI recovery has been limited specifically as a result of the low growth capacity of neurons and a lack of nerve growth factors.

While current SCI treatment focuses on stabilizing the injured area and preventing secondary injury through a combination of surgery, pharmacological intervention, and rehabilitation, the success of treatment has been limited and unable to stimulate spinal cord regeneration. 

Considering the limited success of confidential SCI treatments, several types of stem cells are currently being tested for the treatment of SCI, including mesenchymal stem cells (MSCs) isolated from bone marrow (BMSCs), umbilical cord (UC-MSCs), and adipose tissue (ADSCs).  

In this review, Liau et al. discuss the current status of MSC therapy for SCI, criteria to consider when applying MSC therapy, and review novel biological therapies that can be used together with MSC therapy to enhance its therapeutic potential.

Based on the results of clinical trials, the authors conclude that MSC therapy is beneficial for SCI patients. While not all patients responded to MSC therapy, the authors note that observed improvement varied from patient to patient. In addition to discrepancies attributed to patient variations, source of MSC, route of stem cell administration, timing of cell administration, number of cell administrations, number of cells administered, and cell preparation methods were also observed to affect the efficacy of therapy. 

Despite the delayed progress in phase III trials, there are several new therapeutic treatment strategies that incorporate stem cell secretory product-based therapy, including stem cell secretome therapy, scaffold-based therapy, and immunotherapy. The authors indicate that all of these novel therapeutic approaches may be able to be used in combination with MSC therapy to enhance the therapeutic efficacy of MSCs by improving cell survival, migration, engraftment, and proliferation.

The authors conclude this review by summarizing that, to date, MSC therapy has been demonstrated to be safe but unable to improve neurological function for all treated patients. Despite the limited success of this therapy, other studies are currently underway in an effort to improve the delivery of MSCs and MSC-derived products by utilizing scaffolds or by combining them with immunotherapy to improve the efficacy of the treatment.

Source:  “Treatment of spinal cord injury with mesenchymal stem cells – NCBI.” 22 Sep. 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510077/.

Utilizing Mesenchymal Stem Cells for Spinal Cord Injury Therapy

Utilizing Mesenchymal Stem Cells for Spinal Cord Injury Therapy

Spinal cord injuries (SCI) are the most serious complication associated with spinal injuries and often result in permanent damage to the nervous system. With nearly 300,000 people in the United States living with SCI, the inability to treat these injuries has a significant impact on physical, mental, and financial health. 

Additionally, while 94% of those suffering acute traumatic SCI survive initial treatment for the condition, both long-term survival and quality of life are often reduced as a result of post-injury complications. Further complicating the issue is the fact that the current standard of SCI treatment is designed only to reduce the secondary effects of injury and not directly promote healing through neuroregeneration.

Considering that mesenchymal stem cells (MSCs) are known to have anti-inflammatory properties, promote vascular regeneration, and to release neuro-nutrients, they are becoming increasingly promising as a potential treatment for SCI.

In this article, Xia et al. examine the evidence of pathophysiological changes occurring after SCI, review the underlying mechanisms of MSCs, summarize the potential application of MSCs in clinical practice, and highlight the challenges surrounding the use of MSCs in the treatment of SCI in future applications. 

The goal of any SCI therapeutic treatment option is to promote rapid recovery of neurological function through a combination of medical and surgical interventions. However, to date, there are no optimal treatment strategies that allow for this goal to be met.   

MSCs’ multidirectional differentiation capabilities are highly viable and known to provide structural support in SCI. In terms of using MSCs in the treatment of SCI, and specifically for their role as an anti-inflammatory agent, the most attractive aspect is their unique immunomodulatory ability.

Additionally, the goal of treatment after SCI is to repair the damaged nerve cells and restore nerve function. Studies exploring differentiation of MSCs after SCI have demonstrated spontaneously expressed neuromarkers at SCI sites and have allowed for recovery of neurological function. 

The authors point out that traumatic SCI usually results in the direct destruction of blood vessels around the spinal cord which often results in ischemic necrosis and secondary injuries. Since promoting vascular recovery contributes to the recovery of motor function in patients with SCI, SCI vascular recovery is a new target for the treatment of SCI. Several studies have observed that MSCs secrete angiogenic factors that promote pericyte recruitment, a critical step in vascular maturation. The authors also report recent findings indicating that 57% of the vascular endothelial cells around the SCI of a mouse showed vascular regeneration effects after receiving MSC-EVs with an extensive vascular network formed around the injury over a period of 28 days.

Although MSCs are beneficial to the recovery of neurological function in patients with SCI, the authors call for additional research to focus on better understanding the SCI cellular mechanisms and MSC action for use in clinical practice. Additionally, Xia et al. point out that the survival rate and long-term survival of MSCs in the SCI microenvironment remain an unresolved issue.

MSCs repair SCI through anti-inflammatory effects and by promoting nerve axon regeneration and vascular regeneration. While further research is required to fully understand the mechanism underlying the effect of MSCs, the authors conclude the role of MSCs in treating SCI has been demonstrated in several clinical trials. 

Source: “Mesenchymal stem cells in the treatment of spinal cord injury.” 

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1141601/full.

Phase 1 Clinical Trial Investigating the Use of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Traumatic Spinal Cord Injury

Phase 1 Clinical Trial Investigating the Use of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Traumatic Spinal Cord Injury

With more than 17,000 people in the US sustaining a spinal cord injury (SCI) each year and an estimated combined cost to healthcare and the workforce exceeding $40 billion, the condition has significant personal and socioeconomic implications. In addition, SCIs have limited pharmacological treatment options to support the regeneration of nerve damage.

Considering the limited treatment options for this condition, the field of regenerative medicine, and specifically the use of stem cells, has recently drawn interest as a potential therapeutic treatment option for paralysis resulting from SCIs.

In this report, Bydon et al. summarize findings of the ongoing multidisciplinary phase 1 clinical trial exploring the safety and efficacy of intrathecal autologous adipose tissue-derived (AD) mesenchymal stem cells (MSCs) in patients with blunt, traumatic SCI.

Specifically, as part of this report, the authors describe the outcome of the first patient with C3-4 SCI treated with AD-MSCs. At the time of SCI, neurologic examination revealed complete loss of motor and sensory function below the level of injury; an injury diagnosed as an American Spinal Injury Association (ASIA) grade A SCI. 

After undergoing initial treatment, including C2-6 posterior cervical decompression and fusion, improvement in motor and sensory function was demonstrable. However, neurological gains plateaued 6 months after sustaining injury.

Upon enrollment into the CELLTOP clinical trial 9 months after injury, the patient’s neurologic status was found to be ASIA grade C and imaging revealed bilateral myelomalacia at the C3 level and at the C2-6 decompression and fusion. Additionally, an open biopsy of adipose tissue found in the abdominal wall was performed 8 weeks prior to receiving an initial intrathecal injection. 

After receiving an intrathecal injection of 100 million autologous AD-MSCs 11 months after injury, the patient was observed for clinical signs of efficacy at 3, 6, 12, and 18 months following injection.

Bydon et al. observed progressive improvement in upper extremity motor scores and considerable improvement in lower extremity scores at 18 months following injection. The patient also demonstrated consistent improvement in ASIA sensory score, including improvements in pinprick and light touch scores at follow-up after 18 months. The authors reported patient improvements in Capabilities of Upper Extremity score, quality of life (as measured by Global Health Score), and in physical and occupational therapy measures. Other than a moderate headache on day 2, no other safety issues or adverse events were reported. 

While further clinical trial is required, the authors conclude that intrathecal AD-MSC administration may be a relatively noninvasive and safe therapeutic option for patients with SCI to improve their neurologic status after reaching a ceiling effect in terms of spontaneous recovery.

Source: “First Report From a Phase 1 Trial of Autologous Adipose Tissue ….” 27 Nov. 2019, https://www.mayoclinicproceedings.org/article/S0025-6196(19)30871-7/fulltext

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