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Kabatas S, Civelek E, Boyalı O, Sezen GB, Ozdemir O, Bahar-Ozdemir Y, Kaplan N, Savrunlu EC, Karaöz E. Safety and efficiency of Wharton's Jelly-derived mesenchymal stem cell administration in patients with traumatic brain injury: First results of a phase I study. World J Stem Cells 2024; 16:641-655. [PMID: 38948099 PMCID: PMC11212551 DOI: 10.4252/wjsc.v16.i6.641] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/26/2024] [Accepted: 05/09/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. Stem cell transplantation has evolved as a novel treatment modality in the management of TBI, as it has the potential to arrest the degeneration and promote regeneration of new cells in the brain. Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) have recently shown beneficial effects in the functional recovery of neurological deficits. AIM To evaluate the safety and efficiency of MSC therapy in TBI. METHODS We present 6 patients, 4 male and 2 female aged between 21 and 27 years who suffered a TBI. These 6 patients underwent 6 doses of intrathecal, intramuscular (i.m.) and intravenous transplantation of WJ-MSCs at a target dose of 1 × 106/kg for each application route. Spasticity was assessed using the Modified Ashworth scale (MAS), motor function according to the Medical Research Council Muscle Strength Scale, quality of life was assessed by the Functional Independence Measure (FIM) scale and Karnofsky Performance Status scale. RESULTS Our patients showed only early, transient complications, such as subfebrile fever, mild headache, and muscle pain due to i.m. injection, which resolved within 24 h. During the one year follow-up, no other safety issues or adverse events were reported. These 6 patients showed improvements in their cognitive abilities, muscle spasticity, muscle strength, performance scores and fine motor skills when compared before and after the intervention. MAS values, which we used to assess spasticity, were observed to statistically significantly decrease for both left and right sides (P < 0.001). The FIM scale includes both motor scores (P < 0.05) and cognitive scores (P < 0.001) and showed a significant increase in pretest posttest analyses. The difference observed in the participants' Karnofsky Performance Scale values pre and post the intervention was statistically significant (P < 0.001). CONCLUSION This study showed that cell transplantation has a safe, effective and promising future in the management of TBI.
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Affiliation(s)
- Serdar Kabatas
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Türkiye
- Center for Stem Cell & Gene Therapy Research and Practice, University of Health Sciences Turkey, Istanbul 34255, Türkiye.
| | - Erdinç Civelek
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Türkiye
| | - Osman Boyalı
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Türkiye
| | - Gülseli Berivan Sezen
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Türkiye
| | - Omer Ozdemir
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Türkiye
| | - Yeliz Bahar-Ozdemir
- Department of Physical Medicine and Rehabilitation, Health Sciences University Sultan Abdulhamid Han Training and Research Hospital, Istanbul 34668, Türkiye
| | - Necati Kaplan
- Department of Neurosurgery, Istanbul Rumeli University, Çorlu Reyap Hospital, Tekirdağ 59860, Türkiye
| | - Eyüp Can Savrunlu
- Department of Neurosurgery, Nevşehir State Hospital, Nevşehir 50300, Türkiye
| | - Erdal Karaöz
- Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell), Liv Hospital, Istanbul 34340, Türkiye
- Department of Histology and Embryology, Istinye University, Faculty of Medicine, Istanbul 34010, Türkiye
- Center for Stem Cell and Tissue Engineering Research and Practice, Istinye University, Istanbul 34340, Türkiye
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Kabatas S, Civelek E, Boyalı O, Sezen GB, Ozdemir O, Bahar-Ozdemir Y, Kaplan N, Savrunlu EC, Karaöz E. Safety and efficiency of Wharton’s Jelly-derived mesenchymal stem cell administration in patients with traumatic brain injury: First results of a phase I study. World J Stem Cells 2024; 16:640-654. [DOI: 10.4252/wjsc.v16.i6.640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/26/2024] [Accepted: 05/09/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. Stem cell transplantation has evolved as a novel treatment modality in the management of TBI, as it has the potential to arrest the degeneration and promote regeneration of new cells in the brain. Wharton’s Jelly-derived mesenchymal stem cells (WJ-MSCs) have recently shown beneficial effects in the functional recovery of neurological deficits.
AIM To evaluate the safety and efficiency of MSC therapy in TBI.
METHODS We present 6 patients, 4 male and 2 female aged between 21 and 27 years who suffered a TBI. These 6 patients underwent 6 doses of intrathecal, intramuscular (i.m.) and intravenous transplantation of WJ-MSCs at a target dose of 1 × 106/kg for each application route. Spasticity was assessed using the Modified Ashworth scale (MAS), motor function according to the Medical Research Council Muscle Strength Scale, quality of life was assessed by the Functional Independence Measure (FIM) scale and Karnofsky Performance Status scale.
RESULTS Our patients showed only early, transient complications, such as subfebrile fever, mild headache, and muscle pain due to i.m. injection, which resolved within 24 h. During the one year follow-up, no other safety issues or adverse events were reported. These 6 patients showed improvements in their cognitive abilities, muscle spasticity, muscle strength, performance scores and fine motor skills when compared before and after the intervention. MAS values, which we used to assess spasticity, were observed to statistically significantly decrease for both left and right sides (P < 0.001). The FIM scale includes both motor scores (P < 0.05) and cognitive scores (P < 0.001) and showed a significant increase in pretest posttest analyses. The difference observed in the participants’ Karnofsky Performance Scale values pre and post the intervention was statistically significant (P < 0.001).
CONCLUSION This study showed that cell transplantation has a safe, effective and promising future in the management of TBI.
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Affiliation(s)
- Serdar Kabatas
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Türkiye
- Center for Stem Cell & Gene Therapy Research and Practice, University of Health Sciences Turkey, Istanbul 34255, Türkiye
| | - Erdinç Civelek
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Türkiye
| | - Osman Boyalı
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Türkiye
| | - Gülseli Berivan Sezen
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Türkiye
| | - Omer Ozdemir
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Türkiye
| | - Yeliz Bahar-Ozdemir
- Department of Physical Medicine and Rehabilitation, Health Sciences University Sultan Abdulhamid Han Training and Research Hospital, Istanbul 34668, Türkiye
| | - Necati Kaplan
- Department of Neurosurgery, Istanbul Rumeli University, Çorlu Reyap Hospital, Tekirdağ 59860, Türkiye
| | - Eyüp Can Savrunlu
- Department of Neurosurgery, Nevşehir State Hospital, Nevşehir 50300, Türkiye
| | - Erdal Karaöz
- Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell), Liv Hospital, Istanbul 34340, Türkiye
- Department of Histology and Embryology, Istinye University, Faculty of Medicine, Istanbul 34010, Türkiye
- Center for Stem Cell and Tissue Engineering Research and Practice, Istinye University, Istanbul 34340, Türkiye
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Amirbekyan M, Adhikarla V, Cheng JP, Moschonas EH, Bondi CO, Rockne RC, Kline AE, Gutova M. Neuroprotective potential of intranasally delivered L-myc immortalized human neural stem cells in female rats after a controlled cortical impact injury. Sci Rep 2023; 13:17874. [PMID: 37857701 PMCID: PMC10587115 DOI: 10.1038/s41598-023-44426-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/08/2023] [Indexed: 10/21/2023] Open
Abstract
Efficacious stem cell-based therapies for traumatic brain injury (TBI) depend on successful delivery, migration, and engraftment of stem cells to induce neuroprotection. L-myc expressing human neural stem cells (LMNSC008) demonstrate an inherent tropism to injury sites after intranasal (IN) administration. We hypothesize that IN delivered LMNSC008 cells migrate to primary and secondary injury sites and modulate biomarkers associated with neuroprotection and tissue regeneration. To test this hypothesis, immunocompetent adult female rats received either controlled cortical impact injury or sham surgery. LMNSC008 cells or a vehicle were administered IN on postoperative days 7, 9, 11, 13, 15, and 17. The distribution and migration of eGFP-expressing LMNSC008 cells were quantified over 1 mm-thick optically cleared (CLARITY) coronal brain sections from TBI and SHAM controls. NSC migration was observed along white matter tracts projecting toward the hippocampus and regions of TBI. ELISA and Nanostring assays revealed a shift in tissue gene expression in LMNSC008 treated rats relative to controls. LMNSC008 treatment reduced expression of genes and pathways involved in inflammatory response, microglial function, and various cytokines and receptors. Our proof-of-concept studies, although preliminary, support the rationale of using intranasal delivery of LMNSC008 cells for functional studies in preclinical models of TBI and provide support for potential translatability in TBI patients.
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Affiliation(s)
- Mari Amirbekyan
- Department of Stem Cell Biology and Regenerative Medicine, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Vikram Adhikarla
- Division of Mathematical Oncology and Computational Systems Biology, Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Jeffrey P Cheng
- Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA
- Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA
| | - Eleni H Moschonas
- Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA
- Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
| | - Corina O Bondi
- Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA
- Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
- Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Russell C Rockne
- Division of Mathematical Oncology and Computational Systems Biology, Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Anthony E Kline
- Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA.
- Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
- Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
- Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, USA.
- Critical Care Medicine, and Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
- Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Margarita Gutova
- Department of Stem Cell Biology and Regenerative Medicine, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
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Kim K, Akbas T, Lee R, Manella K, Sulzer J. Self-modulation of rectus femoris reflex excitability in humans. Sci Rep 2023; 13:8134. [PMID: 37208394 DOI: 10.1038/s41598-023-34709-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 05/05/2023] [Indexed: 05/21/2023] Open
Abstract
Hyperreflexia is common after neurological injury such as stroke, yet clinical interventions have had mixed success. Our previous research has shown that hyperreflexia of the rectus femoris (RF) during pre-swing is closely associated with reduced swing phase knee flexion in those with post-stroke Stiff-Knee gait (SKG). Thus, reduction of RF hyperreflexia may improve walking function in those with post-stroke SKG. A non-pharmacological procedure for reducing hyperreflexia has emerged based on operant conditioning of H-reflex, an electrical analog of the spinal stretch reflex. It is currently unknown whether operant conditioning can be applied to the RF. This feasibility study trained 7 participants (5 neurologically intact, 2 post-stroke) to down-condition the RF H-reflex using visual feedback. We found an overall decrease in average RF H-reflex amplitude among all 7 participants (44% drop, p < 0.001, paired t-test), of which the post-stroke individuals contributed (49% drop). We observed a generalized training effect across quadriceps muscles. Post-stroke individuals exhibited improvements in peak knee-flexion velocity, reflex excitability during walking, and clinical measures of spasticity. These outcomes provide promising initial results that operant RF H-reflex conditioning is feasible, encouraging expansion to post-stroke individuals. This procedure could provide a targeted alternative in spasticity management.
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Affiliation(s)
| | | | - Robert Lee
- St. David's Medical Center, Austin, TX, USA
| | | | - James Sulzer
- University of Texas at Austin, Austin, TX, USA.
- MetroHealth Hospital and Case Western Reserve University, Cleveland, OH, USA.
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