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Widodo W, Aprilya D, Satria O. Regenerative Medicine: A New Horizon in Peripheral Nerve Injury and Repair. Orthop Rev (Pavia) 2025; 17:133572. [PMID: 40176924 PMCID: PMC11964392 DOI: 10.52965/001c.133572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 12/21/2024] [Indexed: 04/05/2025] Open
Abstract
A peripheral nerve injury is a great burden for the patient and a challenge for the clinician. In a complete injury (axonotmesis or neurotmesis), the slow nature of nerve regeneration after repair or reconstruction hardly catches up to the target organ's degeneration rate, leading to a poor prognosis. The current advance in regenerative medicine has shown the potency of stem cells and their products for healing many human body structures, including the nerve. A comprehensive literature search was conducted using an internet-based search engine for current advances in regenerative medicine to augment peripheral nerve repair or reconstruction. Stem cells can differentiate into nerve cells and have paracrine and immunomodulatory effects. Its products, such as the secretome and exosome, have also been studied, and they have many benefits for the regeneration process. This novel treatment possesses significant potential to accelerate nerve healing after nerve reconstruction and potentially postpone the degenerative process in the target organ, allowing it to respond to the new signal once nerve regeneration is complete. The aim of this article is to summarized the application of stem cells and its products for nerve healing.
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Affiliation(s)
- Wahyu Widodo
- Hand and Microsurgery Division, Orthopedic and Traumatology Department, Fatmawati General Hospital, Jakarta, Indonesia
| | - Dina Aprilya
- Hand and Microsurgery Division, Orthopedic and Traumatology Department, Fatmawati General Hospital, Jakarta, Indonesia
| | - Oryza Satria
- Hand and Microsurgery Division, Orthopedic and Traumatology Department, Fatmawati General Hospital, Jakarta, Indonesia
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Claessens AAE, Vriend L, Ovadja ZN, Harmsen MC, van Dongen JA, Coert JH. Therapeutic Efficacy of Adipose Tissue-Derived Components in Neuropathic Pain: A Systematic Review. Bioengineering (Basel) 2024; 11:992. [PMID: 39451368 PMCID: PMC11504850 DOI: 10.3390/bioengineering11100992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/02/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Neuropathic pain results from a defect in the somatosensory nervous system caused by a diversity of etiologies. The effect of current treat-ment with analgesics and surgery is limited. Studies report the therapeutic use of adipose tissue-derived components to treat neuropathic pain as a new treatment modality. OBJECTIVE The aim of this systematic review was to investigate the therapeutic clinical efficacy of adipose tissue-derived components on neuro-pathic pain. METHODS PubMed, Medline, Cochrane and Embase databases were searched until August 2023. Clinical studies assessing neuropathic pain after autologous fat grafting or the therapeutic use of adipose tissue-derived com-ponents were included. The outcomes of interest were neuropathic pain and quality of life. RESULTS In total, 433 studies were identified, of which 109 dupli-cates were removed, 324 abstracts were screened and 314 articles were excluded. In total, ten studies were included for comparison. Fat grafting and cellular stromal vascular fraction were used as treatments. Fat grafting indications were post-mastectomy pain syndrome, neuromas, post-herpetic neuropathy, neuro-pathic scar pain and trigeminal neuropathic pain. In seven studies, neuropathic pain levels decreased, and overall, quality of life did not improve. CONCLUSIONS The therapeutic efficacy of adipose tissue-derived components in the treatment of neuropathic pain remains unclear due to the few performed clinical trials with small sample sizes for various indications. Larger and properly designed (randomized) controlled trials are required.
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Affiliation(s)
- Anouk A. E. Claessens
- Department of Plastic, Reconstructive and Hand Surgery, Medisch Centrum Leeuwarden, 8934 AD Leeuwarden, The Netherlands;
| | - Linda Vriend
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht (UMC Utrecht), 3584 CX Utrecht, The Netherlands; (L.V.); (J.A.v.D.); (J.H.C.)
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Zachri N. Ovadja
- Department of Plastic, Reconstructive and Hand Surgery, Medisch Centrum Leeuwarden, 8934 AD Leeuwarden, The Netherlands;
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht (UMC Utrecht), 3584 CX Utrecht, The Netherlands; (L.V.); (J.A.v.D.); (J.H.C.)
| | - Martin C. Harmsen
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Joris. A. van Dongen
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht (UMC Utrecht), 3584 CX Utrecht, The Netherlands; (L.V.); (J.A.v.D.); (J.H.C.)
| | - J. Henk Coert
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht (UMC Utrecht), 3584 CX Utrecht, The Netherlands; (L.V.); (J.A.v.D.); (J.H.C.)
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El Masri J, Fadlallah H, Al Sabsabi R, Afyouni A, Al-Sayegh M, Abou-Kheir W. Adipose-Derived Stem Cell Therapy in Spinal Cord Injury. Cells 2024; 13:1505. [PMID: 39273075 PMCID: PMC11394073 DOI: 10.3390/cells13171505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/04/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
Spinal cord injury (SCI) is a serious condition accompanied by severe adverse events that affect several aspects of the patient's life, such as motor, sensory, and functional impairment. Despite its severe consequences, definitive treatment for these injuries is still missing. Therefore, researchers have focused on developing treatment strategies aimed at ensuring full recovery post-SCI. Accordingly, attention has been drawn toward cellular therapy using mesenchymal stem cells. Considering their wide availability, decreased immunogenicity, wide expansion capacity, and impressive effectiveness in many therapeutic approaches, adipose-derived stem cell (ADSC) injections in SCI cases have been investigated and showed promising results. In this review, SCI pathophysiology and ADSC transplantation benefits are discussed independently, together with SCI animal models and adipose stem cell preparation and application techniques. The mechanisms of healing in an SCI post-ADSC injection, the outcomes of this therapeutic approach, and current clinical trials are also deliberated, in addition to the challenges and future perspectives, aiming to encourage further research in this field.
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Affiliation(s)
- Jad El Masri
- Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon; (J.E.M.); (H.F.)
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon; (R.A.S.); (A.A.)
| | - Hiba Fadlallah
- Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon; (J.E.M.); (H.F.)
| | - Rahaf Al Sabsabi
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon; (R.A.S.); (A.A.)
| | - Ahmad Afyouni
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon; (R.A.S.); (A.A.)
| | - Mohamed Al-Sayegh
- Biology Division, New York University Abu Dhabi, Abu Dhabi 2460, United Arab Emirates
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon; (J.E.M.); (H.F.)
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Selimoglu MN, Kocacan M, Tuncer S, Tosun Z, Erdogan E. Positive effect of ulnar nerve fascicle transfer to musculocutaneous nerve seeded with allogeneic adipose tissue derived stem cells on nerve regeneration for repairing upper brachial plexus injury in a rat model: A preliminary study. Microsurgery 2024; 44:e31208. [PMID: 39012167 DOI: 10.1002/micr.31208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/07/2024] [Accepted: 06/21/2024] [Indexed: 07/17/2024]
Abstract
BACKGROUND Traumatic peripheral nerve injury, with an annual incidence reported to be approximately 13-23 per 100,000 people, is a serious clinical condition that can often lead to significant functional impairment and permanent disability. Although nerve transfer has become increasingly popular in the treatment of brachial plexus injuries, satisfactory results cannot be obtained even with total nerve root transfer, especially after serious injuries. To overcome this problem, we hypothesize that the application of stem cells in conjunction with nerve transfer procedures may be a viable alternative to more aggressive treatments that do not result in adequate improvement. Similarly, some preliminary studies have shown that adipose stem cells combined with acellular nerve allograft provide promising results in the repair of brachial plexus injury. The purpose of this study was to assess the efficacy of combining adipose-derived stem cells with nerve transfer procedure in a rat brachial plexus injury model. METHODS Twenty female Wistar rats weighing 300-350 g and aged 8-10 weeks were randomly divided into two groups: a nerve transfer group (NT group) and a nerve transfer combined adipose stem cell group (NT and ASC group). The upper brachial plexus injury model was established by gently avulsing the C5-C6 roots from the spinal cord with microforceps. A nerve transfer from the ulnar nerve to the musculocutaneous nerve (Oberlin procedure) was performed with or without seeded allogeneic adipose tissue-derived stem cells. Adipose tissue-derived stem cells at a rate of 2 × 106 cells were injected locally to the surface of the nerve transfer area with a 23-gauge needle. Immunohistochemistry (S100 and PGP 9.5 antibodies) and electrophysiological data were used to evaluate the effect of nerve repair 12 weeks after surgery. RESULTS The mean latency was significantly longer in the NT group (2.0 ± 0.0 ms, 95% CI: 1.96-2.06) than in the NT and ASC group (1.7 ± 0.0 ms, 95% CI: 1.7-1.7) (p < .001). The mean peak value was higher in the NT group (1.7 ± 0.0 mV, 95% CI: 1.7-1.7) than in the NT and ASC group (1.7 ± 0.3 mV, 95% CI: 1.6-1.9) with no significant difference (p = .61). Although S100 and PGP 9.5 positive areas were observed in higher amounts in the NT and ASC group compared to the NT group, the differences were not statistically significant (p = .26 and .08, respectively). CONCLUSIONS This study conducted on rats provides preliminary evidence that adipose-derived stem cells may have a positive effect on nerve transfer for the treatment of brachial plexus injury. Further studies with larger sample sizes and longer follow-up periods are needed to confirm these findings.
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Affiliation(s)
| | - Metin Kocacan
- Faculty of Medicine, Department of Histology and Embryology, Dumlupınar University, Kütahya, Turkey
| | - Seçkin Tuncer
- Faculty of Medicine, Department of Biophysics, Osmangazi University, Eskişehir, Turkey
| | - Zekeriya Tosun
- Faculty of Medicine, Department of Plastic, Reconstructive and Aesthetic Surgery, Selcuk University, Konya, Turkey
| | - Ender Erdogan
- Faculty of Medicine, Department of Histology and Embryology, Selcuk University, Konya, Turkey
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Dogny C, André-Lévigne D, Kalbermatten DF, Madduri S. Therapeutic Potential and Challenges of Mesenchymal Stem Cell-Derived Exosomes for Peripheral Nerve Regeneration: A Systematic Review. Int J Mol Sci 2024; 25:6489. [PMID: 38928194 PMCID: PMC11203969 DOI: 10.3390/ijms25126489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/03/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
Gap injuries to the peripheral nervous system result in pain and loss of function, without any particularly effective therapeutic options. Within this context, mesenchymal stem cell (MSC)-derived exosomes have emerged as a potential therapeutic option. Thus, the focus of this study was to review currently available data on MSC-derived exosome-mounted scaffolds in peripheral nerve regeneration in order to identify the most promising scaffolds and exosome sources currently in the field of peripheral nerve regeneration. We conducted a systematic review following PRISMA 2020 guidelines. Exosome origins varied (adipose-derived MSCs, bone marrow MSCs, gingival MSC, induced pluripotent stem cells and a purified exosome product) similarly to the materials (Matrigel, alginate and silicone, acellular nerve graft [ANG], chitosan, chitin, hydrogel and fibrin glue). The compound muscle action potential (CMAP), sciatic functional index (SFI), gastrocnemius wet weight and histological analyses were used as main outcome measures. Overall, exosome-mounted scaffolds showed better regeneration than scaffolds alone. Functionally, both exosome-enriched chitin and ANG showed a significant improvement over time in the sciatica functional index, CMAP and wet weight. The best histological outcomes were found in the exosome-enriched ANG scaffold with a high increase in the axonal diameter and muscle cross-section area. Further studies are needed to confirm the efficacy of exosome-mounted scaffolds in peripheral nerve regeneration.
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Affiliation(s)
- Clelia Dogny
- Department of Plastic, Reconstructive and Aesthetic Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Dominik André-Lévigne
- Department of Plastic, Reconstructive and Aesthetic Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Daniel F. Kalbermatten
- Department of Plastic, Reconstructive and Aesthetic Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
- Bioengineering and Neuroregeneration Laboratory, Department of Surgery, University of Geneva, 1211 Geneva, Switzerland
| | - Srinivas Madduri
- Department of Plastic, Reconstructive and Aesthetic Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
- Bioengineering and Neuroregeneration Laboratory, Department of Surgery, University of Geneva, 1211 Geneva, Switzerland
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Panagopoulos GN, Megaloikonomos PD, Mitsiokapa EA, Bami M, Agrogiannis G, Johnson EO, Soucacos PN, Papagelopoulos PJ, Mavrogenis AF. Adipose-Derived Stem Cells and Tacrolimus Improve Nerve Regeneration in a Rat Sciatic Nerve Defect Model. Orthopedics 2023; 46:e353-e361. [PMID: 37052592 DOI: 10.3928/01477447-20230407-01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
This study compared the effect of undifferentiated adipose-derived stem cells (ADSCs) vs tacrolimus (FK506) in peripheral nerve regeneration in a rat sciatic nerve complete transection model. Forty Wistar rats were equally distributed in four groups. In the SHAM surgery group, the sciatic nerve was exposed and no further intervention was done. In the conduit-alone group (the SLN group), a 10-mm nerve gap was created and bridged with a fibrin conduit filled in with normal saline. In the FK506 group, the fibrin conduit was injected with soluble FK506. In the ADSC group, the conduit was impregnated with undifferentiated ADSCs. Nerve regeneration was assessed by means of walking track analysis, electromyography, and neurohistomorphometry. Clinically and microscopically, nerve regeneration was achieved in all groups at 12 weeks. Walking track analysis confirmed functional recovery in the FK506 and ADSC groups, but there was no difference between them. Recovery in function was also achieved in the SLN group, but it was inferior (P<.05). Electromyography demonstrated superior nerve regeneration in the FK506 and ADSC groups compared with the SLN group (P<.05), with no difference between the FK506 and ADSC groups. Similarly, histology showed no difference between the FK506 and ADSC groups, although both outperformed the SLN group (P<.05). No complications were observed. Successful peripheral nerve regeneration can be accomplished after a 10-mm nerve defect treated with nerve conduits. Superior nerve regeneration may be expected when the conduits are loaded with undifferentiated ADSCs or FK506, with similar outcomes for ADSCs and FK506. [Orthopedics. 2023;46(6):e353-e361.].
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Khaled MM, Ibrahium AM, Abdelgalil AI, El-Saied MA, El-Bably SH. Regenerative Strategies in Treatment of Peripheral Nerve Injuries in Different Animal Models. Tissue Eng Regen Med 2023; 20:839-877. [PMID: 37572269 PMCID: PMC10519924 DOI: 10.1007/s13770-023-00559-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/15/2023] [Accepted: 05/21/2023] [Indexed: 08/14/2023] Open
Abstract
BACKGROUND Peripheral nerve damage mainly resulted from traumatic or infectious causes; the main signs of a damaged nerve are the loss of sensory and/or motor functions. The injured nerve has limited regenerative capacity and is recovered by the body itself, the recovery process depends on the severity of damage to the nerve, nowadays the use of stem cells is one of the new and advanced methods for treatment of these problems. METHOD Following our review, data are collected from different databases "Google scholar, Springer, Elsevier, Egyptian Knowledge Bank, and PubMed" using different keywords such as Peripheral nerve damage, Radial Nerve, Sciatic Nerve, Animals, Nerve regeneration, and Stem cell to investigate the different methods taken in consideration for regeneration of PNI. RESULT This review contains tables illustrating all forms and types of regenerative medicine used in treatment of peripheral nerve injuries (PNI) including different types of stem cells " adipose-derived stem cells, bone marrow stem cells, Human umbilical cord stem cells, embryonic stem cells" and their effect on re-constitution and functional recovery of the damaged nerve which evaluated by physical, histological, Immuno-histochemical, biochemical evaluation, and the review illuminated the best regenerative strategies help in rapid peripheral nerve regeneration in different animal models included horse, dog, cat, sheep, monkey, pig, mice and rat. CONCLUSION Old surgical attempts such as neurorrhaphy, autogenic nerve transplantation, and Schwann cell implantation have a limited power of recovery in cases of large nerve defects. Stem cell therapy including mesenchymal stromal cells has a high potential differentiation capacity to renew and form a new nerve and also restore its function.
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Affiliation(s)
- Mona M Khaled
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Cairo University, Giza Square, Giza, 12211, Egypt.
| | - Asmaa M Ibrahium
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Cairo University, Giza Square, Giza, 12211, Egypt
| | - Ahmed I Abdelgalil
- Department of Surgery, Anaesthesiology and Radiology, Faculty of Veterinary Medicine, Cairo University, Giza Square, Giza, 12211, Egypt
| | - Mohamed A El-Saied
- Department of Pathology, Faculty of Veterinary of Veterinary Medicine, Cairo University, Giza Square, Giza, 12211, Egypt
| | - Samah H El-Bably
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Cairo University, Giza Square, Giza, 12211, Egypt
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Chen SH, Wu CC, Tseng WL, Lu FI, Liu YH, Lin SP, Lin SC, Hsueh YY. Adipose-derived stem cells modulate neuroinflammation and improve functional recovery in chronic constriction injury of the rat sciatic nerve. Front Neurosci 2023; 17:1172740. [PMID: 37457010 PMCID: PMC10339833 DOI: 10.3389/fnins.2023.1172740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/05/2023] [Indexed: 07/18/2023] Open
Abstract
Introduction Compressive neuropathy, a common chronic traumatic injury of peripheral nerves, leads to variable impairment in sensory and motor function. Clinical symptoms persist in a significant portion of patients despite decompression, with muscle atrophy and persistent neuropathic pain affecting 10%-25% of cases. Excessive inflammation and immune cell infiltration in the injured nerve hinder axon regeneration and functional recovery. Although adipose-derived stem cells (ASCs) have demonstrated neural regeneration and immunomodulatory potential, their specific effects on compressive neuropathy are still unclear. Methods We conducted modified CCI models on adult male Sprague-Dawley rats to induce irreversible neuropathic pain and muscle atrophy in the sciatic nerve. Intraneural ASC injection and nerve decompression were performed. Behavioral analysis, muscle examination, electrophysiological evaluation, and immunofluorescent examination of the injured nerve and associated DRG were conducted to explore axon regeneration, neuroinflammation, and the modulation of inflammatory gene expression. Transplanted ASCs were tracked to investigate potential beneficial mechanisms on the local nerve and DRG. Results Persistent neuropathic pain was induced by chronic constriction of the rat sciatic nerve. Local ASC treatment has demonstrated robust beneficial outcomes, including the alleviation of mechanical allodynia, improvement of gait, regeneration of muscle fibers, and electrophysiological recovery. In addition, locally transplanted ASCs facilitated axon remyelination, alleviated neuroinflammation, and reduced inflammatory cell infiltration of the injured nerve and associated dorsal root ganglion (DRG). Trafficking of the transplanted ASC preserved viability and phenotype less than 7 days but contributed to robust immunomodulatory regulation of inflammatory gene expression in both the injured nerve and DRG. Discussion Locally transplanted ASC on compressed nerve improve sensory and motor recoveries from irreversible chronic constriction injury of rat sciatic nerve via alleviation of both local and remote neuroinflammation, suggesting the promising role of adjuvant ASC therapies for clinical compressive neuropathy.
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Affiliation(s)
- Szu-Han Chen
- Division of Plastic and Reconstructive Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Center of Cell Therapy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- International Research Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Ching Wu
- International Research Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wan-Ling Tseng
- Division of Plastic and Reconstructive Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Fu-I Lu
- Department of Biotechnology and Bioindustry Science, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
- The integrative Evolutionary Galliform Genomics (iEGG) and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | - Ya-Hsin Liu
- Department of Life Sciences, National Cheng Kung University, Tainan, Taiwan
| | - Shau-Ping Lin
- Institute of Biotechnology, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan
| | - Sheng-Che Lin
- Division of Plastic Surgery, Department of Surgery, An-Nan Hospital, China Medical University, Tainan, Taiwan
| | - Yuan-Yu Hsueh
- Division of Plastic and Reconstructive Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Center of Cell Therapy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- International Research Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Lischer M, di Summa PG, Petrou IG, Schaefer DJ, Guzman R, Kalbermatten DF, Madduri S. Mesenchymal Stem Cells in Nerve Tissue Engineering: Bridging Nerve Gap Injuries in Large Animals. Int J Mol Sci 2023; 24:ijms24097800. [PMID: 37175506 PMCID: PMC10177884 DOI: 10.3390/ijms24097800] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Cell-therapy-based nerve repair strategies hold great promise. In the field, there is an extensive amount of evidence for better regenerative outcomes when using tissue-engineered nerve grafts for bridging severe gap injuries. Although a massive number of studies have been performed using rodents, only a limited number involving nerve injury models of large animals were reported. Nerve injury models mirroring the human nerve size and injury complexity are crucial to direct the further clinical development of advanced therapeutic interventions. Thus, there is a great need for the advancement of research using large animals, which will closely reflect human nerve repair outcomes. Within this context, this review highlights various stem cell-based nerve repair strategies involving large animal models such as pigs, rabbits, dogs, and monkeys, with an emphasis on the limitations and strengths of therapeutic strategy and outcome measurements. Finally, future directions in the field of nerve repair are discussed. Thus, the present review provides valuable knowledge, as well as the current state of information and insights into nerve repair strategies using cell therapies in large animals.
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Affiliation(s)
- Mirko Lischer
- Center for Bioengineering and Regenerative Medicine, Department of Biomedical Engineering, University of Basel, 4123 Allschwil, Switzerland
| | - Pietro G di Summa
- Department of Plastic, Reconstructive and Hand Surgery, University Hospital of Lausanne and University of Lausanne, 1015 Lausanne, Switzerland
| | - Ilias G Petrou
- Plastic, Reconstructive and Aesthetic Surgery, Department of Surgery, University Hospitals and University of Geneva, 1205 Geneva, Switzerland
| | - Dirk J Schaefer
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
| | - Raphael Guzman
- Department of Neurosurgery, University Hospital Basel, 4031 Basel, Switzerland
| | - Daniel F Kalbermatten
- Plastic, Reconstructive and Aesthetic Surgery, Department of Surgery, University Hospitals and University of Geneva, 1205 Geneva, Switzerland
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
| | - Srinivas Madduri
- Center for Bioengineering and Regenerative Medicine, Department of Biomedical Engineering, University of Basel, 4123 Allschwil, Switzerland
- Plastic, Reconstructive and Aesthetic Surgery, Department of Surgery, University Hospitals and University of Geneva, 1205 Geneva, Switzerland
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
- Bioengineering and Neuroregeneration, Department of Surgery, Geneva University Hospitals and University of Geneva, 1205 Geneva, Switzerland
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Sivanarayanan TB, Bhat IA, Sharun K, Palakkara S, Singh R, Remya, Parmar MS, Bhardwaj R, Chandra V, Munuswamy P, Kinjavdekar P, Pawde AM, Amarpal, Sharma GT. Allogenic bone marrow-derived mesenchymal stem cells and its conditioned media for repairing acute and sub-acute peripheral nerve injuries in a rabbit model. Tissue Cell 2023; 82:102053. [PMID: 36907044 DOI: 10.1016/j.tice.2023.102053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023]
Abstract
The present study evaluated healing potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) and BM-MSCs-conditioned medium (BM-MSCs-CM) for acute and subacute injuries in the rabbit peripheral nerve injury model. The regenerative capacity of MSCs was evaluated in 40 rabbits divided into eight groups, four groups each for acute and subacute injury models. BM-MSCs and BM-MSCS-CM were prepared by isolating allogenic bone marrow from the iliac crest. After inducing sciatic nerve crush injury, different treatments consisting of PBS, Laminin, BM-MSCs + laminin, and BM-MSCS-CM + laminin were used on the day of injury in the acute injury model and after ten days of crush injury in the subacute groups. The parameters studied included: pain, total neurological score, gastrocnemius muscle weight and volume ratio, histopathology of the sciatic nerve and gastrocnemius muscle, and scanning electron microscopy (SEM). Findings indicate that BM-MSCs and BM-MSCS-CM have augmented the regenerative capacity in acute and subacute injury groups with a slightly better improvement in the subacute groups than the animals in acute injury groups. Histopathology data revealed different levels of regenerative process undergoing in the nerve. Neurological observations, gastrocnemius muscle evaluation, muscle histopathology, and the SEM results depicted better healing in animals treated with BM-MSCs and BM-MSCS-CM. With this data, it could be concluded that BM-MSCs support the healing of injured peripheral nerves, and the BM-MSCS-CM does accelerate the healing of acute and subacute peripheral nerve injuries in rabbits. However, stem cell therapy may be indicated during the subacute phase for better results.
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Affiliation(s)
- T B Sivanarayanan
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Irfan Ahmad Bhat
- Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Khan Sharun
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Sangeetha Palakkara
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Rashmi Singh
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Remya
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Mehtab Singh Parmar
- Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Rahul Bhardwaj
- Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Vikash Chandra
- Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Palanivelu Munuswamy
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Prakash Kinjavdekar
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - A M Pawde
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Amarpal
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
| | - G Taru Sharma
- National Institute of Animal Biotechnology, Hyderabad 500032, India.
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11
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Augmenting Peripheral Nerve Regeneration with Adipose-Derived Stem Cells. Stem Cell Rev Rep 2022; 18:544-558. [PMID: 34417730 PMCID: PMC8858329 DOI: 10.1007/s12015-021-10236-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2021] [Indexed: 02/03/2023]
Abstract
Peripheral nerve injuries (PNIs) are common and debilitating, cause significant health care costs for society, and rely predominately on autografts, which necessitate grafting a nerve section non-locally to repair the nerve injury. One possible approach to improving treatment is bolstering endogenous regenerative mechanisms or bioengineering new nervous tissue in the peripheral nervous system. In this review, we discuss critical-sized nerve gaps and nerve regeneration in rats, and summarize the roles of adipose-derived stem cells (ADSCs) in the treatment of PNIs. Several regenerative treatment modalities for PNI are described: ADSCs differentiating into Schwann cells (SCs), ADSCs secreting growth factors to promote peripheral nerve growth, ADSCs promoting myelination growth, and ADSCs treatments with scaffolds. ADSCs' roles in regenerative treatment and features are compared to mesenchymal stem cells, and the administration routes, cell dosages, and cell fates are discussed. ADSCs secrete neurotrophic factors and exosomes and can differentiate into Schwann cell-like cells (SCLCs) that share features with naturally occurring SCs, including the ability to promote nerve regeneration in the PNS. Future clinical applications are also discussed.
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12
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Facilitatory effects of artificial nerve filled with adipose-derived stem cell sheets on peripheral nerve regeneration: An experimental study. J Orthop Sci 2021; 26:1113-1118. [PMID: 33248872 DOI: 10.1016/j.jos.2020.09.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 08/25/2020] [Accepted: 09/16/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND We evaluated how artificial nerves filled with adipose-derived stem cell (ADSC) sheets could facilitate peripheral nerve regeneration. METHODS We prepared ADSC sheets following previously described protocols. We transected the sciatic nerve in 12-week-old Wistar rats, fixed the nerve ends to the artificial conduit, and prepared three groups: (1) conduits alone (control group); (2) conduits filled with ADSCs (ADSCs group), and (3) conduits filled with ADSC sheets (ADSC sheet group). We assessed the subjects 4 and 12 weeks post-transplantation (n = 24). We investigated βIII-tubulin and anti-S100 expression at 4 and 12 weeks post-transplantation, in longitudinal- and cross-sections of the central portion in the regenerated tissues. The vascular endothelial growth factor A (VEGFA) and neuregulin-1 expressions were analyzed using real-time reverse-transcription polymerase chain reaction (real-time RT-PCR). We evaluated the tibialis anterior muscle wet weight (affected/healthy sides, %) and sciatic function index (SFI) 12 weeks post-transplantation. RESULTS The ADSC sheet group comprised more S100-positive cells than the other groups. The regenerated axon length in the ADSC sheet group was markedly the longest among the studied groups. The immunostaining revealed a positive area in the regenerated tissue center in all groups, tending to be the largest in the ADSC sheet group. The muscle wet weight indicated that the ADSC sheet group exhibited significantly higher weight than the control. The mean SFI showed that the ADSC sheet group exhibited significantly better results than the control. The VEGFA expression was higher both in the ADSC and the ADSC sheet group than in the control. The neuregulin-1 expression was higher both in the ADSC and the ADSC sheet group than in the control. CONCLUSIONS The ADSC sheets could potentially support transplanting an adequate number of ADSCs at the target site. Compared with the conventional method of attaching ADSCs, the use of ADSC sheets promotes accelerated nerve regeneration.
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13
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Weiss JB, Phillips CJ, Malin EW, Gorantla VS, Harding JW, Salgar SK. Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies. Ann Med Surg (Lond) 2021; 71:102917. [PMID: 34703584 PMCID: PMC8524106 DOI: 10.1016/j.amsu.2021.102917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 10/05/2021] [Indexed: 11/04/2022] Open
Abstract
Background Optimizing nerve regeneration and re-innervation of target muscle/s is the key for improved functional recovery following peripheral nerve damage. We investigated whether administration of mesenchymal stem cell (MSC), Granulocyte-Colony Stimulating Factor (G-CSF) and/or Dihexa can improve recovery of limb function following peripheral nerve damage in rat sciatic nerve transection-repair model. Materials and methods There were 10 experimental groups (n = 6–8 rats/group). Bone marrow derived syngeneic MSCs (2 × 106; passage≤6), G-CSF (200–400 μg/kg b.wt.), Dihexa (2–4 mg/kg b.wt.) and/or Vehicle were administered to male Lewis rats locally via hydrogel at the site of nerve repair, systemically (i.v./i.p), and/or to gastrocnemius muscle. The limb sensory and motor functions were assessed at 1–2 week intervals post nerve repair until the study endpoint (16 weeks). Results The sensory function in all nerve boundaries (peroneal, tibial, sural) returned to nearly normal by 8 weeks (Grade 2.7 on a scale of Grade 0–3 [0 = No function; 3 = Normal function]) in all groups combined. The peroneal nerve function recovered quickly with return of function at one week (∼2.0) while sural nerve function recovered rather slowly at four weeks (∼1.0). Motor function at 8–16 weeks post-nerve repair as determined by walking foot print grades significantly (P < 0.05) improved with MSC + G-CSF or MSC + Dihexa administrations into gastrocnemius muscle and mitigated foot flexion contractures. Conclusions These findings demonstrate MSC, G-CSF and Dihexa are promising candidates for adjunct therapies to promote limb functional recovery after surgical nerve repair, and have implications in peripheral nerve injury and limb transplantation. IACUC No.215064.
G-CSF in combination with MSCs improved limb function recovery in sciatic nerve transection- repair model. Dihexa in combination with MSC improved limb function recovery in sciatic nerve transection- repair model. Foot flexion contractures were reduced with G-CSF & MSC or Dihexa & MSC administration into target muscle gastrocnemius. MSC, G-CSF or Dihexa combination therapy is attractive, feasible & promising in peripheral nerve injury repair and have implications in limb transplantation. The findings warrant further investigation to understand the cellular/molecular mechanisms.
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Affiliation(s)
- Jessica B Weiss
- Department of Surgery, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, USA
| | - Cody J Phillips
- Department of Surgery, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, USA
| | - Edward W Malin
- Department of Surgery, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, USA
| | - Vijay S Gorantla
- Department of Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Joseph W Harding
- Department of Integrative Physiology & Neuroscience, Washington State University, Pullman, WA, USA
| | - Shashikumar K Salgar
- Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, USA
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14
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Huang Q, Cai Y, Zhang X, Liu J, Liu Z, Li B, Wong H, Xu F, Sheng L, Sun D, Qin J, Luo Z, Lu X. Aligned Graphene Mesh-Supported Double Network Natural Hydrogel Conduit Loaded with Netrin-1 for Peripheral Nerve Regeneration. ACS APPLIED MATERIALS & INTERFACES 2021; 13:112-122. [PMID: 33397079 DOI: 10.1021/acsami.0c16391] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The gold standard treatment for peripheral nerve injuries (PNIs) is the autologous graft, while it is associated with the shortage of donors and results in major complications. In the present study, we engineer a graphene mesh-supported double-network (DN) hydrogel scaffold, loaded with netrin-1. Natural alginate and gelatin-methacryloyl entangled hydrogel that is synthesized via fast exchange of ions and ultraviolet irradiation provide proper mechanical strength and excellent biocompatibility and can also serve as a reservoir for netrin-1. Meanwhile, the graphene mesh can promote the proliferation of Schwann cells and guide their alignments. This approach allows scaffolds to have an acceptable Young's modulus of 725.8 ± 46.52 kPa, matching with peripheral nerves, as well as a satisfactory electrical conductivity of 6.8 ± 0.85 S/m. In addition, netrin-1 plays a dual role in directing axon pathfinding and neuronal migration that optimizes the tube formation ability at a concentration of 100 ng/mL. This netrin-1-loaded graphene mesh tube/DN hydrogel nerve scaffold can significantly promote the regeneration of peripheral nerves and the restoration of denervated muscle, which is even superior to autologous grafts. Our findings may provide an effective therapeutic strategy for PNI patients that can replace the scarce autologous graft.
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Affiliation(s)
- Qun Huang
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yuting Cai
- Department of Materials Science and Engineering, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China
- Department of Chemical and Biological Engineering, and William Mong Institute of Nano Science and Technology, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon 999077, Hong Kong, China
| | - Xing Zhang
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Junchao Liu
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Zhenjing Liu
- Department of Chemical and Biological Engineering, and William Mong Institute of Nano Science and Technology, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon 999077, Hong Kong, China
| | - Bo Li
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Hoilun Wong
- Department of Chemical and Biological Engineering, and William Mong Institute of Nano Science and Technology, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon 999077, Hong Kong, China
| | - Feng Xu
- Bioinspired Engineering and Biomechanics Center, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Liyuan Sheng
- Shenzhen Institute, Peking University, Shenzhen 518057, China
| | - Dazhi Sun
- Department of Materials Science and Engineering, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China
| | - Jinbao Qin
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Vascular Center of Shanghai Jiao Tong University, Shanghai 200011, China
| | - Zhengtang Luo
- Department of Chemical and Biological Engineering, and William Mong Institute of Nano Science and Technology, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon 999077, Hong Kong, China
| | - Xinwu Lu
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Vascular Center of Shanghai Jiao Tong University, Shanghai 200011, China
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15
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Lavorato A, Raimondo S, Boido M, Muratori L, Durante G, Cofano F, Vincitorio F, Petrone S, Titolo P, Tartara F, Vercelli A, Garbossa D. Mesenchymal Stem Cell Treatment Perspectives in Peripheral Nerve Regeneration: Systematic Review. Int J Mol Sci 2021; 22:E572. [PMID: 33430035 PMCID: PMC7827385 DOI: 10.3390/ijms22020572] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 12/14/2022] Open
Abstract
Traumatic peripheral nerve lesions affect hundreds of thousands of patients every year; their consequences are life-altering and often devastating and cause alterations in movement and sensitivity. Spontaneous peripheral nerve recovery is often inadequate. In this context, nowadays, cell therapy represents one of the most innovative approaches in the field of nerve repair therapies. The purpose of this systematic review is to discuss the features of different types of mesenchymal stem cells (MSCs) relevant for peripheral nerve regeneration after nerve injury. The published literature was reviewed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A combination of the keywords "nerve regeneration", "stem cells", "peripheral nerve injury", "rat", and "human" were used. Additionally, a "MeSH" research was performed in PubMed using the terms "stem cells" and "nerve regeneration". The characteristics of the most widely used MSCs, their paracrine potential, targeted stimulation, and differentiation potentials into Schwann-like and neuronal-like cells are described in this paper. Considering their ability to support and stimulate axonal growth, their remarkable paracrine activity, their presumed differentiation potential, their extremely low immunogenicity, and their high survival rate after transplantation, ADSCs appear to be the most suitable and promising MSCs for the recovery of peripheral nerve lesion. Clinical considerations are finally reported.
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Affiliation(s)
- Andrea Lavorato
- Neurosurgery Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, TO, Italy; (F.C.); (F.V.); (S.P.); (D.G.)
| | - Stefania Raimondo
- Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano, TO, Italy; (S.R.); (L.M.)
| | - Marina Boido
- Department of Neuroscience “Rita Levi Montalcini”, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano, TO, Italy; (M.B.); (A.V.)
| | - Luisa Muratori
- Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano, TO, Italy; (S.R.); (L.M.)
| | - Giorgia Durante
- Faculty of Medicine and Surgery, University of Turin, 10126 Turin, TO, Italy;
| | - Fabio Cofano
- Neurosurgery Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, TO, Italy; (F.C.); (F.V.); (S.P.); (D.G.)
| | - Francesca Vincitorio
- Neurosurgery Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, TO, Italy; (F.C.); (F.V.); (S.P.); (D.G.)
| | - Salvatore Petrone
- Neurosurgery Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, TO, Italy; (F.C.); (F.V.); (S.P.); (D.G.)
| | - Paolo Titolo
- Traumatology–Reconstructive Microsurgery, Department of Orthopaedics and Traumatology, CTO Hospital, 10126 Turin, TO, Italy;
| | - Fulvio Tartara
- Neurosurgery Unit, Istituto Clinico Città Studi (ICCS), 20131 Milan, MI, Italy;
| | - Alessandro Vercelli
- Department of Neuroscience “Rita Levi Montalcini”, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano, TO, Italy; (M.B.); (A.V.)
| | - Diego Garbossa
- Neurosurgery Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, TO, Italy; (F.C.); (F.V.); (S.P.); (D.G.)
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16
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Krzesniak NE, Sarnowska A, Figiel-Dabrowska A, Osiak K, Domanska-Janik K, Noszczyk BH. Secondary release of the peripheral nerve with autologous fat derivates benefits for functional and sensory recovery. Neural Regen Res 2021; 16:856-864. [PMID: 33229720 PMCID: PMC8178762 DOI: 10.4103/1673-5374.297081] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The reconstruction of nerve continuity after traumatic nerve injury is the gold standard in hand surgery. Immediate, tension-free, end-to-end nerve suture ensures the best prognosis. The recovery is mostly promising; however, in a few cases, insufficient outcomes in motor or sensory function are observed. Intra- and extra-fascicular scarring accompanies the nerve regeneration process and limits final outcomes. Secondary nerve release in those cases is recommended. Unfortunately, scarring recurrence cannot be eliminated after secondary revision and neurolysis. The supportive influences of mesenchymal stem cells in the process of nerve regeneration were observed in many preclinical studies. However, a limited number of studies in humans have analyzed the clinical usage of mesenchymal stem cells in peripheral nerve reconstruction and revisions. The objective of this study was to evaluate the effects of undifferentiated adipose-derived stromal/stem cell injection during a last-chance surgery (neurolysis, nerve release) on a previously reconstructed nerve. Three patients (one female, two males; mean age 59 ± 4.5 years at the time of injury), who experienced failure of reconstructions of median and ulnar nerves, were included in this study. During the revision surgery, nerve fascicles were released, and adipose-derived stromal/stem cells were administered through microinjections along the fascicles and around the adjacent tissues after external neurolysis. During 36 months of follow-up, patients noticed gradual signs of sensory and in consequence functional recovery. No adverse effects were observed. Simultaneous nerve release with adipose-derived stromal/stem cells support is a promising method in patients who need secondary nerve release after nerve reconstruction. This method can constitute an alternative procedure in patients experiencing recovery failure and allow improvement in cases of limited nerve regeneration. The study protocol was approved by the Institutional Review Board (IRB) at the Centre of Postgraduate Medical Education (No. 62/PB/2016) on September 14, 2016.
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Affiliation(s)
- Natalia E Krzesniak
- Department of Plastic and Reconstructive Surgery, Center of Postgraduate Medical Education, Prof. W. Orlowski Memorial Hospital, Warsaw, Poland
| | - Anna Sarnowska
- Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland
| | | | - Katarzyna Osiak
- Department of Plastic and Reconstructive Surgery, Center of Postgraduate Medical Education, Prof. W. Orlowski Memorial Hospital, Warsaw, Poland
| | | | - Bartłomiej H Noszczyk
- Department of Plastic and Reconstructive Surgery, Center of Postgraduate Medical Education, Prof. W. Orlowski Memorial Hospital, Warsaw, Poland
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17
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Shah S, Mudigonda S, Mitha AP, Salo P, Krawetz RJ. Epidural fat mesenchymal stem cells: Important microenvironmental regulators in health, disease, and regeneration: Do EF-MSCs play a role in dural homeostasis/maintenance? Bioessays 2020; 43:e2000215. [PMID: 33191529 DOI: 10.1002/bies.202000215] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/01/2020] [Accepted: 10/06/2020] [Indexed: 12/26/2022]
Abstract
Mesenchymal stem cells (MSCs) are present in fat tissues throughout the body, yet little is known regarding their biological role within epidural fat. We hypothesize that debridement of epidural fat and/or subsequent loss of MSCs within this tissue, disrupts homeostasis in the vertebral environment resulting in increased inflammation, fibrosis, and decreased neovascularization leading to poorer functional outcomes post-injury/operatively. Clinically, epidural fat is commonly considered a space-filling tissue with limited functionality and therefore typically discarded during surgery. However, the presence of MSCs within epidural fat suggests that itis more biologically active than historically believed and may contribute to the regulation of homeostasis and regeneration in the dural environment. While the current literature supports our hypothesis, it will require additional experimentation to determine if epidural fat is an endogenous driver of repair and regeneration and if so, this tissue should be minimally perturbed from its original location in the spinal canal. Also see the video abstract here https://youtu.be/MIol_IWK1os.
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Affiliation(s)
- Sophia Shah
- McCaig institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.,Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta, Canada
| | - Sathvika Mudigonda
- McCaig institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada
| | - Alim P Mitha
- Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta, Canada.,Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Paul Salo
- McCaig institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.,Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Roman J Krawetz
- McCaig institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.,Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta, Canada.,Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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18
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Prautsch KM, Schmidt A, Paradiso V, Schaefer DJ, Guzman R, Kalbermatten DF, Madduri S. Modulation of Human Adipose Stem Cells' Neurotrophic Capacity Using a Variety of Growth Factors for Neural Tissue Engineering Applications: Axonal Growth, Transcriptional, and Phosphoproteomic Analyses In Vitro. Cells 2020; 9:E1939. [PMID: 32839392 PMCID: PMC7565501 DOI: 10.3390/cells9091939] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/11/2020] [Accepted: 08/19/2020] [Indexed: 12/16/2022] Open
Abstract
We report on a potential strategy involving the exogenous neurotrophic factors (NTF) for enhancing the neurotrophic capacity of human adipose stem cells (ASC) in vitro. For this, ASC were stimulated for three days using NTF, i.e., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), NT4, glial cell-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF). The resulting conditioned medium (CM) as well as individual NTF exhibited distinct effects on axonal outgrowth from dorsal root ganglion (DRG) explants. In particular, CM derived from NT3-stimulated ASC (CM-NT3-ASC) promoted robust axonal outgrowth. Subsequent transcriptional analysis of DRG cultures in response to CM-NT3-ASC displayed significant upregulation of STAT-3 and GAP-43. In addition, phosphoproteomic analysis of NT3-stimulated ASC revealed significant changes in the phosphorylation state of different proteins that are involved in cytokine release, growth factors signaling, stem cell maintenance, and differentiation. Furthermore, DRG cultures treated with CM-NT3-ASC exhibited significant changes in the phosphorylation levels of proteins involved in tubulin and actin cytoskeletal pathways, which are crucial for axonal growth and elongation. Thus, the results obtained at the transcriptional, proteomic, and cellular level reveal significant changes in the neurotrophic capacity of ASC following NT3 stimulation and provide new options for improving the axonal growth-promoting potential of ASC in vitro.
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Affiliation(s)
- Katharina M. Prautsch
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Spitalstrasse 21, 4021 Basel, Switzerland; (K.M.P.); (D.J.S.); (D.F.K.)
- Department of Pathology, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
- Department of Biomedical Engineering, University of Basel, Gewerbestrasse 14, 4123 Allschwil, Switzerland
| | - Alexander Schmidt
- Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland;
| | - Viola Paradiso
- Department of Pathology, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
| | - Dirk J. Schaefer
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Spitalstrasse 21, 4021 Basel, Switzerland; (K.M.P.); (D.J.S.); (D.F.K.)
- Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
| | - Raphael Guzman
- Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
- Department of Neurosurgery, University Hospital Basel, Spitalstrasse 21, 4021 Basel, Switzerland
| | - Daniel F. Kalbermatten
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Spitalstrasse 21, 4021 Basel, Switzerland; (K.M.P.); (D.J.S.); (D.F.K.)
- Department of Pathology, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
- Department of Biomedical Engineering, University of Basel, Gewerbestrasse 14, 4123 Allschwil, Switzerland
| | - Srinivas Madduri
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Spitalstrasse 21, 4021 Basel, Switzerland; (K.M.P.); (D.J.S.); (D.F.K.)
- Department of Pathology, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
- Department of Biomedical Engineering, University of Basel, Gewerbestrasse 14, 4123 Allschwil, Switzerland
- Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
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19
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Grafts of human adipose-derived stem cells into a biodegradable poly (acid lactic) conduit enhances sciatic nerve regeneration. Brain Res 2020; 1747:147026. [PMID: 32750328 DOI: 10.1016/j.brainres.2020.147026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/20/2020] [Accepted: 07/19/2020] [Indexed: 12/29/2022]
Abstract
Despite the regenerative potential of the Peripheral Nervous System (PNS), injuries with loss of a nerve segment make the functional recovery a challenge. This work aimed to investigate the effects of the association of biodegradable conduits of poly (lactic acid) (PLA) with human adipose-derived stem cells (hADSCs) on the regeneration of the sciatic nerve. C57BL / 6 male mice were submitted to sciatic nerve transection followed by tubulization with PLA conduit. Animals were allocated in two groups: the first received an injection of DMEM inside the conduit (DMEM) and the second received hADSCs inside it (hADSC). Sensory and motor functions were assessed by the pinprick test and electroneuromiography, respectively. To assess neuronal survival the retrograde tracer fluorogold was injected into the sciatic nerve distally to the lesion site. One week after that, animals were sacrificed, tissues harvested and processed for morphological evaluation. After eight weeks, all animals showed sensory recovery in the pinprick test and there was no significant difference between the two groups. The amplitude of the compound muscle action potential was higher in the hADSCs group. The number of myelinated nerve fibers, muscle cells and motor plates was higher in the hADSC group. There was also greater survival of sensory and motor neurons in the hADSC animals. These results suggest that the association of PLA conduit and cell therapy with hADSCs leads to a better functional and morphological recovery after sciatic nerve transection.
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20
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Pro-angiogenic scaffold-free Bio three-dimensional conduit developed from human induced pluripotent stem cell-derived mesenchymal stem cells promotes peripheral nerve regeneration. Sci Rep 2020; 10:12034. [PMID: 32694698 PMCID: PMC7374629 DOI: 10.1038/s41598-020-68745-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 06/26/2020] [Indexed: 02/07/2023] Open
Abstract
Although autologous nerve grafting is widely accepted as the gold standard treatment for segmental nerve defects, harvesting autologous nerves is highly invasive and leads to functional loss of the ablated part. In response, artificial nerve conduits made of artificial materials have been reported, but the efficacy of the nerve regeneration still needs improvement. The purpose of this study is to investigate the efficacy and mechanism of the Bio three-dimensional (3D) conduit composed of xeno-free human induced pluripotent stem cell–derived mesenchymal stem cells (iMSCs). The 5-mm nerve gap of the sciatic nerve in immunodeficient rats was bridged with the Bio 3D conduit or silicone tube. Functional and histological recovery were assessed at 8 weeks after surgery. The regenerated nerve in the Bio 3D group was significantly superior to that in the silicone group based on morphology, kinematics, electrophysiology, and wet muscle weight. Gene expression analyses demonstrated neurotrophic and angiogenic factors. Macroscopic observation revealed neovascularization both inside and on the surface of the Bio 3D conduit. Upon their subcutaneous implantation, iMSCs could induce angiogenesis. The Bio 3D conduit fabricated from iMSCs are an effective strategy for nerve regeneration in animal model. This technology will be useful in future clinical situations.
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21
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Ex-Vivo Stimulation of Adipose Stem Cells by Growth Factors and Fibrin-Hydrogel Assisted Delivery Strategies for Treating Nerve Gap-Injuries. Bioengineering (Basel) 2020; 7:bioengineering7020042. [PMID: 32380789 PMCID: PMC7357460 DOI: 10.3390/bioengineering7020042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/01/2020] [Accepted: 05/03/2020] [Indexed: 12/22/2022] Open
Abstract
Peripheral nerve injuries often result in lifelong disabilities despite advanced surgical interventions, indicating the urgent clinical need for effective therapies. In order to improve the potency of adipose-derived stem cells (ASC) for nerve regeneration, the present study focused primarily on ex-vivo stimulation of ASC by using growth factors, i.e., nerve growth factor (NGF) or vascular endothelial growth factor (VEGF) and secondly on fibrin-hydrogel nerve conduits (FNC) assisted ASC delivery strategies, i.e., intramural vs. intraluminal loading. ASC were stimulated by NGF or VEGF for 3 days and the resulting secretome was subsequently evaluated in an in vitro axonal outgrowth assay. For the animal study, a 10 mm sciatic nerve gap-injury was created in rats and reconstructed using FNC loaded with ASC. Secretome derived from NGF-stimulated ASC promoted significant axonal outgrowth from the DRG-explants in comparison to all other conditions. Thus, NGF-stimulated ASC were further investigated in animals and found to enhance early nerve regeneration as evidenced by the increased number of β-Tubulin III+ axons. Notably, FNC assisted intramural delivery enabled the improvement of ASC’s therapeutic efficacy in comparison to the intraluminal delivery system. Thus, ex-vivo stimulation of ASC by NGF and FNC assisted intramural delivery may offer new options for developing effective therapies.
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22
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Rbia N, Bulstra LF, Friedrich PF, Bishop AT, Nijhuis TH, Shin AY. Gene expression and growth factor analysis in early nerve regeneration following segmental nerve defect reconstruction with a mesenchymal stromal cell-enhanced decellularized nerve allograft. PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2020; 8:e2579. [PMID: 32095395 PMCID: PMC7015582 DOI: 10.1097/gox.0000000000002579] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 10/21/2019] [Indexed: 12/16/2022]
Abstract
The purpose of this study was to evaluate the molecular mechanisms underlying nerve repair by a decellularized nerve allograft seeded with adipose-derived mesenchymal stromal cells (MSCs) and compare it to the unseeded allograft and autograft nerve. METHODS Undifferentiated MSCs were seeded onto decellularized nerve allografts and used to reconstruct a 10 mm gap in a rat sciatic nerve model. Gene expression profiles of genes essential for nerve regeneration and immunohistochemical staining (IHC) for PGP9.5, NGF, RECA-1, and S100 were obtained 2 weeks postoperatively. RESULTS Semi-quantitative RT-PCR analysis showed that the angiogenic molecule VEGFA was significantly increased in seeded allografts, and transcription factor SOX2 was downregulated in seeded allografts. Seeded grafts showed a significant increase in immunohistochemical markers NGF and RECA-1, when compared with unseeded allografts. CONCLUSIONS MSCs contributed to the secretion of trophic factors. A beneficial effect of the MSCs on angiogenesis was found when compared with the unseeded nerve allograft, but implanted MSCs did not show evidence of differentiation into Schwann cell-like cells.
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Affiliation(s)
- Nadia Rbia
- From the Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minn
- Department of Plastic, Reconstructive and Hand Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Liselotte F. Bulstra
- From the Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minn
- Department of Plastic, Reconstructive and Hand Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Allen T. Bishop
- From the Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minn
| | - Tim H.J. Nijhuis
- Department of Plastic, Reconstructive and Hand Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Alexander Y. Shin
- From the Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minn
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23
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The Cellular and Molecular Patterns Involved in the Neural Differentiation of Adipose-Derived Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1298:23-41. [PMID: 32514816 DOI: 10.1007/5584_2020_547] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Injuries to the nervous system cause serious problems among affected patients by preventing them from the possibility of living a normal life. As this tissue possesses a reduced capacity of self-regeneration currently, lots of different strategies are being developed in order to make the regeneration in the nervous system possible. Among them, tissue engineering and stem cell-based therapies are to date very exploded fields and tremendous progress has been made in this direction. As the two main components of the nervous system, react differently to injuries and behave different during disease, it is clear that two separate regeneration approaches have been taken into consideration during development of treatment. Special attention is constantly given to the potential of adipose-derived stem cells for this kind of application. Due to the fact that they present remarkable properties, they can easily be obtained and have demonstrated that are capable of engaging in neural and glial lineages, adipose-derived stem cells are promising tools for the field of nervous system regeneration. Moreover, new insights into epigenetic control and modifications during the differentiation of adipose-derived stem cells towards the neural liege could provide new methods to maximize the regeneration process. In this review, we summarize the current applications of adipose-derived stem cells for neural regeneration and discuss in-depth molecular patterns involved in the differentiation of adipose-derived stem cells in neuron-like cells and Schwann-like cells.
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24
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Carvalho CR, Oliveira JM, Reis RL. Modern Trends for Peripheral Nerve Repair and Regeneration: Beyond the Hollow Nerve Guidance Conduit. Front Bioeng Biotechnol 2019; 7:337. [PMID: 31824934 PMCID: PMC6882937 DOI: 10.3389/fbioe.2019.00337] [Citation(s) in RCA: 182] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 10/30/2019] [Indexed: 12/13/2022] Open
Abstract
Peripheral nerve repair and regeneration remains among the greatest challenges in tissue engineering and regenerative medicine. Even though peripheral nerve injuries (PNIs) are capable of some degree of regeneration, frail recovery is seen even when the best microsurgical technique is applied. PNIs are known to be very incapacitating for the patient, due to the deprivation of motor and sensory abilities. Since there is no optimal solution for tackling this problem up to this day, the evolution in the field is constant, with innovative designs of advanced nerve guidance conduits (NGCs) being reported every day. As a basic concept, a NGC should act as a physical barrier from the external environment, concomitantly acting as physical guidance for the regenerative axons across the gap lesion. NGCs should also be able to retain the naturally released nerve growth factors secreted by the damaged nerve stumps, as well as reducing the invasion of scar tissue-forming fibroblasts to the injury site. Based on the neurobiological knowledge related to the events that succeed after a nerve injury, neuronal subsistence is subjected to the existence of an ideal environment of growth factors, hormones, cytokines, and extracellular matrix (ECM) factors. Therefore, it is known that multifunctional NGCs fabricated through combinatorial approaches are needed to improve the functional and clinical outcomes after PNIs. The present work overviews the current reports dealing with the several features that can be used to improve peripheral nerve regeneration (PNR), ranging from the simple use of hollow NGCs to tissue engineered intraluminal fillers, or to even more advanced strategies, comprising the molecular and gene therapies as well as cell-based therapies.
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Affiliation(s)
- Cristiana R. Carvalho
- 3B's Research Group, I3Bs – Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Avepark, Guimarães, Portugal
| | - Joaquim M. Oliveira
- 3B's Research Group, I3Bs – Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Avepark, Guimarães, Portugal
| | - Rui L. Reis
- 3B's Research Group, I3Bs – Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Avepark, Guimarães, Portugal
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25
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Adipose Stem Cell-Based Clinical Strategy for Neural Regeneration: A Review of Current Opinion. Stem Cells Int 2019; 2019:8502370. [PMID: 31827536 PMCID: PMC6885831 DOI: 10.1155/2019/8502370] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/02/2019] [Accepted: 11/11/2019] [Indexed: 02/05/2023] Open
Abstract
Nerve injury is a critical problem in the clinic. Nerve injury causes serious clinic issues including pain and dysfunctions for patients. The disconnection between damaged neural fibers and muscles will result in muscle atrophy in a few weeks if no treatment is applied. Moreover, scientists have discovered that nerve injury can affect the osteogenic differentiation of skeletal stem cells (SSCs) and the fracture repairing. In plastic surgery, muscle atrophy and bone fracture after nerve injury have plagued clinicians for many years. How to promote neural regeneration is the core issue of research in the recent years. Without obvious effects of traditional neurosurgical treatments, research on stem cells in the past 10 years has provided a new therapeutic strategy for us to address this problem. Adipose stem cells (ASCs) are a kind of mesenchymal stem cells that have differentiation potential in adipose tissue. In the recent years, ASCs have become the focus of regenerative medicine. They play a pivotal role in tissue regeneration engineering. As a type of stem cell, ASCs are becoming popular for neuroregenerative medicine due to their advantages and characteristics. In the various diseases of the nervous system, ASCs are gradually applied to treat the related diseases. This review article focuses on the mechanism and clinical application of ASCs in nerve regeneration as well as the related research on ASCs over the past decades.
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26
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Stocchero IN, Lizier NF, Stelini RF, de Oliveira OCG, de Oliveira PRG, Ayoub CA, Rotta TD, Stocchero GF, Kharmandayan P. A Reliable Stem Cell Carrier: An Experimental Study in Wistar Rats. Aesthetic Plast Surg 2019; 43:1353-1361. [PMID: 31399823 DOI: 10.1007/s00266-019-01469-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 07/29/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Treatments based on cell biology need reliable and precise carriers for reaching the desired targets. For that reason, a PDO-based cell carrier was idealized, with the purpose of carrying stem cells to distant sites at room temperature. MATERIALS AND METHODS Three modalities of the same carrier were evaluated: one containing undifferentiated human dental pulp stem cells (DPSCs); one loaded with stem cells induced to neurogenic differentiation (DPSCNs); and one without cells (Blank). The carriers were implanted in sciatic nerve gaps in 48 Wistar rats that were divided in three groups. Two other rats were included in a SHAM control group. Immunohistochemical, histological and clinical analyses were performed in two, four, six and eight weeks of time. RESULTS Efficacy of human stem cell transportation at room temperature to rats was attested. Moreover, it was possible to confirm that those cells show tropism for inflamed environments and are also prone to induction of neurogenesis in the first two weeks, vanishing after that period. CONCLUSION Clinical evaluation of the animals' gait recovery shows a promising perspective of success with the inclusion of stem cell-loaded PDO tubes in nerve gaps, which may be positively compared to previously published studies. NO LEVEL ASSIGNED This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors - www.springer.com/00266.
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Affiliation(s)
- Ithamar Nogueira Stocchero
- State University of Campinas Medical Sciences School - UNICAMP, Campinas, SP, Brazil.
- , São Paulo, Brazil.
| | - Nelson Foresto Lizier
- Biotechnologist Centro de Criogenia Brasil, Avenida Indianópolis, 1843, São Paulo, SP, 04063-003, Brazil
| | - Rafael Fantelli Stelini
- Department of Pathologic Anatomy, UNICAMP, Rua Tessália Vieira de Camargo, 126 Cidade Universitária, Campinas, SP, 13083-887, Brazil
| | | | | | - Carlos Alexandre Ayoub
- Centro de Criogenia Brasil, Avenida Indianópolis, 1843, São Paulo, SP, 04063-003, Brazil
| | - Tainah Desuó Rotta
- Department of Pathologic Anatomy, UNICAMP, Rua Tessália Vieira de Camargo, 126 Cidade Universitária, Campinas, SP, 13083-887, Brazil
| | | | - Paulo Kharmandayan
- Division of Plastic and Reconstructive Surgery, State University of Campinas Medical Sciences School, Rua Tessália Vieira de Camargo, 126 Cidade Universitária, Campinas, SP, 13083-887, Brazil
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27
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Salehi M, Bagher Z, Kamrava SK, Ehterami A, Alizadeh R, Farhadi M, Falah M, Komeili A. Alginate/chitosan hydrogel containing olfactory ectomesenchymal stem cells for sciatic nerve tissue engineering. J Cell Physiol 2019; 234:15357-15368. [PMID: 30701533 DOI: 10.1002/jcp.28183] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/10/2019] [Indexed: 01/24/2023]
Abstract
Regeneration and functional recovery after peripheral nerve damage still remain a significant clinical problem. In this study, alginate/chitosan (alg/chit) hydrogel was used for the transplantation of olfactory ectomesenchymal stem cells (OE-MSCs) to promote peripheral nerve regeneration. The OE-MSCs were isolated from olfactory mucosa biopsies and evaluated by different cell surface markers and differentiation capacity. After creating sciatic nerve injury in a rat model, OE-MSCs were transplanted to the injured area with alg/chit hydrogel which was prepared and well-characterized. The prepared hydrogel had the porosity of 91.3 ± 1.27%, the swelling ratio of 379% after 240 min, weight loss percentages of 80 ± 5.56% after 14 days, and good blood compatibility. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, 4',6-diamidino-2-phenylindole, and LIVE/DEAD staining were done to assay the behavior of OE-MSCs on alg/chit hydrogel and the results confirmed that the hydrogel can provide a suitable substrate for cell survival. For functional analysis, alg/chit hydrogel with and without OE- MSCs was injected into a 3-mm sciatic nerve defect of Wistar rats. The results of the sciatic functional index, hot plate latency, electrophysiological assessment, weight-loss percentage of wet gastrocnemius muscle, and histopathological examination using hematoxylin-eosin and Luxol fast blue staining showed that utilizing alg/chit hydrogel with OE-MSCs to the sciatic nerve defect enhance regeneration compared to the control group and hydrogel without cells.
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Affiliation(s)
- Majid Salehi
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.,Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Zohreh Bagher
- ENT and Head & Neck Research Center and Department, The Five Senses Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Kamran Kamrava
- ENT and Head & Neck Research Center and Department, The Five Senses Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Arian Ehterami
- Department of Mechanical and Aerospace Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Rafieh Alizadeh
- ENT and Head & Neck Research Center and Department, The Five Senses Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Farhadi
- ENT and Head & Neck Research Center and Department, The Five Senses Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Falah
- ENT and Head & Neck Research Center and Department, The Five Senses Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Komeili
- Applied Biophotonics Research Center, Science and Research Branch, Islamic Azad University, Tehran, Iran
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28
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Mitsuzawa S, Ikeguchi R, Aoyama T, Takeuchi H, Yurie H, Oda H, Ohta S, Ushimaru M, Ito T, Tanaka M, Kunitomi Y, Tsuji M, Akieda S, Nakayama K, Matsuda S. The Efficacy of a Scaffold-free Bio 3D Conduit Developed from Autologous Dermal Fibroblasts on Peripheral Nerve Regeneration in a Canine Ulnar Nerve Injury Model: A Preclinical Proof-of-Concept Study. Cell Transplant 2019; 28:1231-1241. [PMID: 31185736 PMCID: PMC6767885 DOI: 10.1177/0963689719855346] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Autologous nerve grafting is widely accepted as the gold standard treatment for segmental
nerve defects. To overcome the inevitable disadvantages of the original method,
alternative methods such as the tubulization technique have been developed. Several
studies have investigated the characteristics of an ideal nerve conduit in terms of
supportive cells, scaffolds, growth factors, and vascularity. Previously, we confirmed
that biological scaffold-free conduits fabricated from human dermal fibroblasts promote
nerve regeneration in a rat sciatic nerve injury model. The purpose of this study is to
evaluate the feasibility of biological scaffold-free conduits composed of autologous
dermal fibroblasts using a large-animal model. Six male beagle dogs were used in this
study. Eight weeks before surgery, dermal fibroblasts were harvested from their groin skin
and grown in culture. Bio 3D conduits were assembled from proliferating dermal fibroblasts
using a Bio 3D printer. The ulnar nerve in each dog’s forelimb was exposed under general
anesthesia and sharply cut to create a 5 mm interstump gap, which was bridged by the
prepared 8 mm Bio 3D conduit. Ten weeks after surgery, nerve regeneration was
investigated. Electrophysiological studies detected compound muscle action potentials
(CMAPs) of the hypothenar muscles and motor nerve conduction velocity (MNCV) in all
animals. Macroscopic observation showed regenerated ulnar nerves. Low-level hypothenar
muscle atrophy was confirmed. Immunohistochemical, histological, and morphometric studies
confirmed the existence of many myelinated axons through the Bio 3D conduit. No severe
adverse event was reported. Hypothenar muscles were re-innervated by regenerated nerve
fibers through the Bio 3D conduit. The scaffold-free Bio 3D conduit fabricated from
autologous dermal fibroblasts is effective for nerve regeneration in a canine ulnar nerve
injury model. This technology was feasible as a treatment for peripheral nerve injury and
segmental nerve defects in a preclinical setting.
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Affiliation(s)
- Sadaki Mitsuzawa
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Ryosuke Ikeguchi
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomoki Aoyama
- Department of Physical Therapy, Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hisataka Takeuchi
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirofumi Yurie
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroki Oda
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Souichi Ohta
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Mika Ushimaru
- Institute for Advancement of Clinical Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Tatsuya Ito
- Institute for Advancement of Clinical Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Mai Tanaka
- Department of Physical Therapy, Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | | | | | | | - Koichi Nakayama
- Department of Regenerative Medicine and Biomedical Engineering Faculty of Medicine, Saga University, Saga, Japan
| | - Shuichi Matsuda
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
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29
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Passipieri JA, Dienes J, Frank J, Glazier J, Portell A, Venkatesh KP, Bliley JM, Grybowski D, Schilling BK, Marra KG, Christ GJ. Adipose Stem Cells Enhance Nerve Regeneration and Muscle Function in a Peroneal Nerve Ablation Model. Tissue Eng Part A 2019; 27:297-310. [PMID: 30760135 DOI: 10.1089/ten.tea.2018.0244] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Severe peripheral nerve injuries have devastating consequences on the quality of life in affected patients, and they represent a significant unmet medical need. Destruction of nerve fibers results in denervation of targeted muscles, which, subsequently, undergo progressive atrophy and loss of function. Timely restoration of neural innervation to muscle fibers is crucial to the preservation of muscle homeostasis and function. The goal of this study was to evaluate the impact of addition of adipose stem cells (ASCs) to polycaprolactone (PCL) nerve conduit guides on peripheral nerve repair and functional muscle recovery in the setting of a critical size nerve defect. To this end, peripheral nerve injury was created by surgically ablating 6 mm of the common peroneal nerve in a rat model. A PCL nerve guide, filled with ASCs and/or poloxamer hydrogel, was sutured to the nerve ends. Negative and positive controls included nerve ablation only (no repair), and reversed polarity autograft nerve implant, respectively. Tibialis anterior (TA) muscle function was assessed at 4, 8, and 12 weeks postinjury, and nerve and muscle tissue was retrieved at the 12-week terminal time point. Inclusion of ASCs in the PCL nerve guide elicited statistically significant time-dependent increases in functional recovery (contraction) after denervation; ∼25% higher than observed in acellular (poloxamer-filled) implants and indistinguishable from autograft implants, respectively, at 12 weeks postinjury (p < 0.05, n = 7-8 in each group). Analysis of single muscle fiber cross-sectional area (CSA) revealed that ASC-based treatment of nerve injury provided a better recapitulation of the overall distribution of muscle fiber CSAs observed in the contralateral TA muscle of uninjured limbs. In addition, the presence of ASCs was associated with improved features of re-innervation distal to the defect, with respect to neurofilament and S100 (Schwann cell marker) expression. In conclusion, these initial studies indicate significant benefits of inclusion of ASCs to the rate and magnitude of both peripheral nerve regeneration and functional recovery of muscle contraction, to levels equivalent to autograft implantation. These findings have important implications to improved nerve repair, and they provide input for future work directed to restoration of nerve and muscle function after polytraumatic injury. Impact Statement This works explores the application of adipose stem cells (ASCs) for peripheral nerve regeneration in a rat model. Herein, we demonstrate that the addition of ASCs in poloxamer-filled PCL nerve guide conduits impacts nerve regeneration and recovery of muscle function, to levels equivalent to autograft implantation, which is considered to be the current gold standard treatment. This study builds on the importance of a timely restoration of innervation to muscle fibers for preservation of muscle homeostasis, and it will provide input for future work aiming at restoring nerve and muscle function after polytraumatic injury.
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Affiliation(s)
- Juliana A Passipieri
- Biomedical Engineering Department, University of Virginia, Charlottesville, Virginia
| | - Jack Dienes
- Biomedical Engineering Department, University of Virginia, Charlottesville, Virginia
| | - Joseph Frank
- Biomedical Engineering Department, University of Virginia, Charlottesville, Virginia
| | - Joshua Glazier
- Biomedical Engineering Department, University of Virginia, Charlottesville, Virginia
| | - Andrew Portell
- Biomedical Engineering Department, University of Virginia, Charlottesville, Virginia
| | - Kaushik P Venkatesh
- Department of Bioengineering and University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jacqueline M Bliley
- Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Damian Grybowski
- Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Benjamin K Schilling
- Department of Bioengineering and University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Kacey G Marra
- Department of Bioengineering and University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.,McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - George J Christ
- Biomedical Engineering Department, University of Virginia, Charlottesville, Virginia.,Orthopaedics Department, University of Virginia, Charlottesville, Virginia
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30
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Sun AX, Prest TA, Fowler JR, Brick RM, Gloss KM, Li X, DeHart M, Shen H, Yang G, Brown BN, Alexander PG, Tuan RS. Conduits harnessing spatially controlled cell-secreted neurotrophic factors improve peripheral nerve regeneration. Biomaterials 2019; 203:86-95. [DOI: 10.1016/j.biomaterials.2019.01.038] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 12/15/2018] [Accepted: 01/24/2019] [Indexed: 02/07/2023]
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31
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Bingham JR, Kniery KR, Jorstad NL, Horkayne-Szakaly I, Hoffer ZS, Salgar SK. "Stem cell therapy to promote limb function recovery in peripheral nerve damage in a rat model" - Experimental research. Ann Med Surg (Lond) 2019; 41:20-28. [PMID: 31011420 PMCID: PMC6463551 DOI: 10.1016/j.amsu.2019.03.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 02/26/2019] [Accepted: 03/24/2019] [Indexed: 02/06/2023] Open
Abstract
Background Optimizing nerve regeneration and mitigating muscle atrophy are the keys to successful outcomes in peripheral nerve damage. We investigated whether mesenchymal stem cell (MSC) therapy can improve limb function recovery in peripheral nerve damage. Materials and methods We used sciatic nerve transection/repair (SNR) and individual nerve transection/repair (INR; branches of sciatic nerve - tibial, peroneal, sural) models to study the effect of MSCs on proximal and distal peripheral nerve damages, respectively, in male Lewis rats. Syngeneic MSCs (5 × 106; passage≤6) or saline were administered locally and intravenously. Sensory/motor functions (SF/MF) of the limb were assessed. Results Rat MSCs (>90%) were CD29+, CD90+, CD34−, CD31− and multipotent. Total SF at two weeks post-SNR & INR with or without MSC therapy was ∼1.2 on a 0–3 grading scale (0 = No function; 3 = Normal); by 12 weeks it was 2.6–2.8 in all groups (n ≥ 9/group). MSCs accelerated SF onset. At eight weeks post-INR, sciatic function index (SFI), a measure of MF (0 = Normal; −100 = Nonfunctional) was −34 and −77 in MSC and vehicle groups, respectively (n ≥ 9); post-SNR it was −72 and −92 in MSC and vehicle groups, respectively. Long-term MF (24 weeks) was apparent in MSC treated INR (SFI -63) but not in SNR (SFI -100). Gastrocnemius muscle atrophy was significantly reduced (P < 0.05) in INR. Nerve histomorphometry revealed reduced axonal area (P < 0.01) but no difference in myelination (P > 0.05) in MSC treated INR compared to the naive contralateral nerve. Conclusion MSC therapy in peripheral nerve damage appears to improve nerve regeneration, mitigate flexion-contractures, and promote limb functional recovery.
Mesenchymal stem cell (MSC) therapy improved limb functional recovery. MSCs improved nerve regeneration and mitigated foot flexion-contractures. Limb muscle atrophy was significantly reduced in individual nerve repair (INR). Functional recovery in distal nerve repair (INR) was superior to proximal (SNR). MSC therapy is attractive, feasible & promising in peripheral nerve injury repair.
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Affiliation(s)
- Jason R Bingham
- Department of Surgery, Madigan Army Medical Center, Tacoma, WA, 98431, USA
| | - Kevin R Kniery
- Department of Surgery, Madigan Army Medical Center, Tacoma, WA, 98431, USA
| | - Nikolas L Jorstad
- Department of Pathology, University of Washington, Seattle, WA, 98195, USA
| | - Iren Horkayne-Szakaly
- Department of Neuropathology & Ophthalmic Pathology, Joint Pathology Center, Defense Health Agency, Silver Spring, MD, 20910, USA
| | - Zachary S Hoffer
- Department of Pathology, Madigan Army Medical Center, Tacoma, WA, 98431, USA
| | - Shashikumar K Salgar
- Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, WA, 98431, USA
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Ying CC, Yang M, Wang Y, Guo YL, Hu WL, Zheng XM. Neural-like cells from adipose-derived stem cells for cavernous nerve injury in rats. Neural Regen Res 2019; 14:1085-1090. [PMID: 30762023 PMCID: PMC6404503 DOI: 10.4103/1673-5374.250630] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Although the remaining nerve tissue can regenerate and partly restore erectile function when the cavernous nerve is compressed/severed and function lost, the limited regenerative ability of these nerve tissues often fails to meet clinical needs. Adipose-derived stem cells are easy to obtain and culture, and can differentiate into neural cells. Their proliferation rate is easy to control and they may be used to help restore injured cavernous nerve function. Sprague-Dawley male rats (n = 45) were equally randomized into three groups: fifteen rats as a sham-operated group, fifteen rats as a bilateral nerve crush (BINC) group (with no further intervention), fifteen rats as a BINC with intracavernous injection of one million neural-like cells from adipose-derived stem cells (NAS) (BINC + NAS) group. After 4 weeks, erectile function was assessed by stimulating the cavernous body. The number of myelinated axons in the dorsal cavernous nerve was determined by toluidine blue staining. The area of neuronal nitric oxide synthase-positive fibers in the dorsal penile nerve was measured by immunohistochemical staining. Masson staining was used to analyze the ratio of smooth muscle to collagen in penile tissue. The results demonstrate that maximal intracavernous pressure, the ratio of maximal intracavernous pressure to mean arterial pressure, the numbers of myelinated axons and neuronal nitric oxide synthase-positive fibers in the dorsal penile nerve, and the ratio of smooth muscle to collagen could be increased after cell transplantation. These findings indicate that neural-like cells from adipose-derived stem cells can effectively alleviate cavernous nerve injury and improve erectile function. All animal experiments were approved by the Animal Ethics Committee of Huazhong University of Science and Technology, China (approval No. 2017-1925) on September 15, 2017.
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Affiliation(s)
- Cheng-Cheng Ying
- Department of Urology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Mei Yang
- Department of Endocrinology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, Hubei Province, China
| | - Yong Wang
- Department of Urology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yong-Lian Guo
- Department of Urology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Wan-Li Hu
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Xin-Min Zheng
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
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Sarker M, Naghieh S, McInnes AD, Schreyer DJ, Chen X. Regeneration of peripheral nerves by nerve guidance conduits: Influence of design, biopolymers, cells, growth factors, and physical stimuli. Prog Neurobiol 2018; 171:125-150. [DOI: 10.1016/j.pneurobio.2018.07.002] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 07/24/2018] [Accepted: 07/26/2018] [Indexed: 01/10/2023]
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Gur S, Abdel-Mageed AB, Sikka SC, Hellstrom WJG. Advances in stem cell therapy for erectile dysfunction. Expert Opin Biol Ther 2018; 18:1137-1150. [PMID: 30301368 DOI: 10.1080/14712598.2018.1534955] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Stem cell (SC) application is a promising area of research in regenerative medicine, with the potential to treat, prevent, and cure disease. In recent years, the number of studies focusing on SCs for the treatment of erectile dysfunction (ED) and other sexual dysfunctions has increased significantly. AREAS COVERED This review includes critical ED targets and preclinical studies, including the use of SCs and animal models in diabetes, aging, cavernous nerve injury, and Peyronie's disease. A literature search was performed on PubMed for English articles. EXPERT OPINION Combination treatment offers better results than monotherapy to improve pathological changes in diabetic ED. Regenerative medicine is a promising approach for the maintenance of sexual health and erectile function later in life. Cavernous nerve regeneration and vascular recovery employing SC treatment may be focused on radical prostatectomy-induced ED. Notwithstanding, there are a number of hurdles to overcome before SC-based therapies for ED are considered in clinical settings. Paracrine action, not cellular differentiation, appears to be the principal mechanism of action underlying SC treatment of ED. Intracavernosal injection of a single SC type should be the choice protocol for future clinical trials.
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Affiliation(s)
- Serap Gur
- a Department of Urology , Tulane University Health Sciences Center , New Orleans , LA , USA.,b Department of Pharmacology, Faculty of Pharmacy , Ankara University , Ankara , Turkey
| | - Asim B Abdel-Mageed
- a Department of Urology , Tulane University Health Sciences Center , New Orleans , LA , USA
| | - Suresh C Sikka
- a Department of Urology , Tulane University Health Sciences Center , New Orleans , LA , USA
| | - Wayne J G Hellstrom
- a Department of Urology , Tulane University Health Sciences Center , New Orleans , LA , USA
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Uz M, Das SR, Ding S, Sakaguchi DS, Claussen JC, Mallapragada SK. Advances in Controlling Differentiation of Adult Stem Cells for Peripheral Nerve Regeneration. Adv Healthc Mater 2018; 7:e1701046. [PMID: 29656561 DOI: 10.1002/adhm.201701046] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 01/08/2018] [Indexed: 01/01/2023]
Abstract
Adult stems cells, possessing the ability to grow, migrate, proliferate, and transdifferentiate into various specific phenotypes, constitute a great asset for peripheral nerve regeneration. Adult stem cells' ability to undergo transdifferentiation is sensitive to various cell-to-cell interactions and external stimuli involving interactions with physical, mechanical, and chemical cues within their microenvironment. Various studies have employed different techniques for transdifferentiating adult stem cells from distinct sources into specific lineages (e.g., glial cells and neurons). These techniques include chemical and/or electrical induction as well as cell-to-cell interactions via co-culture along with the use of various 3D conduit/scaffold designs. Such scaffolds consist of unique materials that possess controllable physical/mechanical properties mimicking cells' natural extracellular matrix. However, current limitations regarding non-scalable transdifferentiation protocols, fate commitment of transdifferentiated stem cells, and conduit/scaffold design have required new strategies for effective stem cells transdifferentiation and implantation. In this progress report, a comprehensive review of recent advances in the transdifferentiation of adult stem cells via different approaches along with multifunctional conduit/scaffolds designs is presented for peripheral nerve regeneration. Potential cellular mechanisms and signaling pathways associated with differentiation are also included. The discussion with current challenges in the field and an outlook toward future research directions is concluded.
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Affiliation(s)
- Metin Uz
- Department of Chemical and Biological Engineering Iowa State University Ames IA 50011 USA
| | - Suprem R. Das
- Department of Mechanical Engineering Iowa State University Ames IA 50011 USA
- Division of Materials Science and Engineering Ames Laboratory Ames IA 50011 USA
| | - Shaowei Ding
- Department of Mechanical Engineering Iowa State University Ames IA 50011 USA
| | - Donald S. Sakaguchi
- Neuroscience Program Iowa State University Ames IA 50011 USA
- Department of Genetics Development and Cell Biology Iowa State University Ames IA 50011 USA
| | - Jonathan C. Claussen
- Department of Mechanical Engineering Iowa State University Ames IA 50011 USA
- Division of Materials Science and Engineering Ames Laboratory Ames IA 50011 USA
| | - Surya K. Mallapragada
- Department of Chemical and Biological Engineering Iowa State University Ames IA 50011 USA
- Department of Genetics Development and Cell Biology Iowa State University Ames IA 50011 USA
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McGrath AM, Brohlin M, Wiberg R, Kingham PJ, Novikov LN, Wiberg M, Novikova LN. Long-Term Effects of Fibrin Conduit with Human Mesenchymal Stem Cells and Immunosuppression after Peripheral Nerve Repair in a Xenogenic Model. CELL MEDICINE 2018; 10:2155179018760327. [PMID: 32634185 PMCID: PMC6172997 DOI: 10.1177/2155179018760327] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 01/07/2018] [Accepted: 01/12/2018] [Indexed: 12/22/2022]
Abstract
Introduction: Previously we showed that a fibrin glue conduit with human mesenchymal stem cells
(hMSCs) and cyclosporine A (CsA) enhanced early nerve regeneration. In this study long
term effects of this conduit are investigated. Methods: In a rat model, the sciatic nerve was repaired with fibrin conduit containing fibrin
matrix, fibrin conduit containing fibrin matrix with CsA treatment and fibrin conduit
containing fibrin matrix with hMSCs and CsA treatment, and also with nerve graft as
control. Results: At 12 weeks 34% of motoneurons of the control group regenerated axons through the
fibrin conduit. CsA treatment alone or with hMSCs resulted in axon regeneration of 67%
and 64% motoneurons respectively. The gastrocnemius muscle weight was reduced in the
conduit with fibrin matrix. The treatment with CsA or CsA with hMSCs induced recovery of
the muscle weight and size of fast type fibers towards the levels of the nerve graft
group. Discussion: The transplantation of hMSCs for peripheral nerve injury should be optimized to
demonstrate their beneficial effects. The CsA may have its own effect on nerve
regeneration.
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Affiliation(s)
- Aleksandra M McGrath
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.,Department of Surgical and Perioperative Science, Section for Hand and Plastic Surgery, Norrland's University Hospital, Umeå, Sweden
| | - Maria Brohlin
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.,Department of Clinical Microbiology, Infection and Immunology, Umeå University, Umeå, Sweden
| | - Rebecca Wiberg
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.,Department of Surgical and Perioperative Science, Section for Hand and Plastic Surgery, Norrland's University Hospital, Umeå, Sweden
| | - Paul J Kingham
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden
| | - Lev N Novikov
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden
| | - Mikael Wiberg
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.,Department of Surgical and Perioperative Science, Section for Hand and Plastic Surgery, Norrland's University Hospital, Umeå, Sweden
| | - Liudmila N Novikova
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden
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Du J, Chen H, Qing L, Yang X, Jia X. Biomimetic neural scaffolds: a crucial step towards optimal peripheral nerve regeneration. Biomater Sci 2018; 6:1299-1311. [PMID: 29725688 PMCID: PMC5978680 DOI: 10.1039/c8bm00260f] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Peripheral nerve injury is a common disease that affects more than 20 million people in the United States alone and remains a major burden to society. The current gold standard treatment for critical-sized nerve defects is autologous nerve graft transplantation; however, this method is limited in many ways and does not always lead to satisfactory outcomes. The limitations of autografts have prompted investigations into artificial neural scaffolds as replacements, and some neural scaffold devices have progressed to widespread clinical use; scaffold technology overall has yet to be shown to be consistently on a par with or superior to autografts. Recent advances in biomimetic scaffold technologies have opened up many new and exciting opportunities, and novel improvements in material, fabrication technique, scaffold architecture, and lumen surface modifications that better reflect biological anatomy and physiology have independently been shown to benefit overall nerve regeneration. Furthermore, biomimetic features of neural scaffolds have also been shown to work synergistically with other nerve regeneration therapy strategies such as growth factor supplementation, stem cell transplantation, and cell surface glycoengineering. This review summarizes the current state of neural scaffolds, highlights major advances in biomimetic technologies, and discusses future opportunities in the field of peripheral nerve regeneration.
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Affiliation(s)
- Jian Du
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. ; Tel: +1 410-706-5025
| | - Huanwen Chen
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. ; Tel: +1 410-706-5025
| | - Liming Qing
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. ; Tel: +1 410-706-5025
| | - Xiuli Yang
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. ; Tel: +1 410-706-5025
| | - Xiaofeng Jia
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. ; Tel: +1 410-706-5025
- Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Zhang R, Rosen JM. The role of undifferentiated adipose-derived stem cells in peripheral nerve repair. Neural Regen Res 2018; 13:757-763. [PMID: 29862994 PMCID: PMC5998619 DOI: 10.4103/1673-5374.232457] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2018] [Indexed: 12/12/2022] Open
Abstract
Peripheral nerve injuries impose significant health and economic consequences, yet no surgical repair can deliver a complete recovery of sensory or motor function. Traditional methods of repair are less than ideal: direct coaptation can only be performed when tension-free repair is possible, and transplantation of nerve autograft can cause donor-site morbidity and neuroma formation. Cell-based therapy delivered via nerve conduits has thus been explored as an alternative method of nerve repair in recent years. Stem cells are promising sources of the regenerative core material in a nerve conduit because stem cells are multipotent in function, abundant in supply, and more accessible than the myelinating Schwann cells. Among different types of stem cells, undifferentiated adipose-derived stem cell (uASC), which can be processed from adipose tissue in less than two hours, is a promising yet underexplored cell type. Studies of uASC have emerged in the past decade and have shown that autologous uASCs are non-immunogenic, easy to access, abundant in supply, and efficacious at promoting nerve regeneration. Two theories have been proposed as the primary regenerative mechanisms of uASC: in situ trans-differentiation towards Schwann cells, and secretion of trophic and anti-inflammatory factors. Future studies need to fully elucidate the mechanisms, side effects, and efficacy of uASC-based nerve regeneration so that uASCs can be utilized in clinical settings.
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Affiliation(s)
- Rui Zhang
- Dartmouth Geisel School of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
| | - Joseph M. Rosen
- Dartmouth Geisel School of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
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Allbright KO, Bliley JM, Havis E, Kim D, Dibernardo GA, Grybowski D, Waldner M, James IB, Sivak WN, Rubin JP, Marra KG. Delivery of adipose‐derived stem cells in poloxamer hydrogel improves peripheral nerve regeneration. Muscle Nerve 2018; 58:251-260. [DOI: 10.1002/mus.26094] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/05/2018] [Indexed: 12/17/2022]
Affiliation(s)
- Kassandra O. Allbright
- Department of Plastic Surgery, School of MedicineUniversity of Pittsburgh3550 Terrace Street 6B, Scaife Hall Pittsburgh Pennsylvania15261 USA
| | - Jacqueline M. Bliley
- Department of Plastic Surgery, School of MedicineUniversity of Pittsburgh3550 Terrace Street 6B, Scaife Hall Pittsburgh Pennsylvania15261 USA
| | - Emmanuelle Havis
- Department of Plastic Surgery, School of MedicineUniversity of Pittsburgh3550 Terrace Street 6B, Scaife Hall Pittsburgh Pennsylvania15261 USA
| | - Deok‐Yeol Kim
- Department of Plastic Surgery, School of MedicineUniversity of Pittsburgh3550 Terrace Street 6B, Scaife Hall Pittsburgh Pennsylvania15261 USA
| | - Gabriella A. Dibernardo
- Department of Plastic Surgery, School of MedicineUniversity of Pittsburgh3550 Terrace Street 6B, Scaife Hall Pittsburgh Pennsylvania15261 USA
| | - Damian Grybowski
- Department of Plastic Surgery, School of MedicineUniversity of Pittsburgh3550 Terrace Street 6B, Scaife Hall Pittsburgh Pennsylvania15261 USA
| | - Matthias Waldner
- Department of Plastic Surgery, School of MedicineUniversity of Pittsburgh3550 Terrace Street 6B, Scaife Hall Pittsburgh Pennsylvania15261 USA
| | - Isaac B. James
- Department of Plastic Surgery, School of MedicineUniversity of Pittsburgh3550 Terrace Street 6B, Scaife Hall Pittsburgh Pennsylvania15261 USA
| | - Wesley N. Sivak
- Department of Plastic Surgery, School of MedicineUniversity of Pittsburgh3550 Terrace Street 6B, Scaife Hall Pittsburgh Pennsylvania15261 USA
| | - J. Peter Rubin
- Department of Plastic Surgery, School of MedicineUniversity of Pittsburgh3550 Terrace Street 6B, Scaife Hall Pittsburgh Pennsylvania15261 USA
| | - Kacey G. Marra
- Department of Plastic Surgery, School of MedicineUniversity of Pittsburgh3550 Terrace Street 6B, Scaife Hall Pittsburgh Pennsylvania15261 USA
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Dabrowska S, Sypecka J, Jablonska A, Strojek L, Wielgos M, Domanska-Janik K, Sarnowska A. Neuroprotective Potential and Paracrine Activity of Stromal Vs. Culture-Expanded hMSC Derived from Wharton Jelly under Co-Cultured with Hippocampal Organotypic Slices. Mol Neurobiol 2017; 55:6021-6036. [PMID: 29134515 PMCID: PMC5994221 DOI: 10.1007/s12035-017-0802-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/12/2017] [Indexed: 01/01/2023]
Abstract
Regardless of enormous translational progress in stem cell clinical application, our knowledge about biological determinants of transplantation-related protection is still limited. In addition to adequate selection of the cell source well dedicated to a specific disease and optimal standardization of all other pre-transplant procedures, we have decided to focus more attention to the impact of culture time and environment itself on molecular properties and regenerative capacity of cell cultured in vitro. The aim of this investigation was to determine neuroprotection-linked cell phenotypic and functional changes that could spontaneously take place when freshly isolated Wharton’s jelly mesenchymal stem cell (WJ-MSC) undergo standard selection, growth, and spontaneous differentiation throughout passaging in vitro. For determining their neuroprotective potential, we used experimental model of human WJ-MSC co-culture with intact or oxygen-glucose-deprived (OGD) rat organotypic hippocampal culture (OHC). It has been shown that putative molecular mechanisms mediating regenerative interactions between WJ-MSC and OHC slices relies mainly on mesenchymal cell paracrine activity. Interestingly, it has been also found that the strongest protective effect is exerted by the co-culture with freshly isolated umbilical cord tissue fragments and by the first cohort of human mesenchymal stem cells (hMSCs) migrating out of these fragments (passage 0). Culturing of WJ-derived hMSC in well-controlled standard conditions under air atmosphere up to fourth passage caused unexpected decline of neuroprotective cell effectiveness toward OGD-OHC in the co-culture model. This further correlated with substantial changes in the WJ-MSC phenotype, profile of their paracrine activities as well as with the recipient tissue reaction evaluated by changes in the rat-specific neuroprotection-linked gene expression.
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Affiliation(s)
- Sylwia Dabrowska
- Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, Warsaw, Poland
| | - Joanna Sypecka
- Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, Warsaw, Poland
| | - Anna Jablonska
- Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, Warsaw, Poland
| | - Lukasz Strojek
- Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, Warsaw, Poland
| | - Miroslaw Wielgos
- 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland
| | - Krystyna Domanska-Janik
- Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, Warsaw, Poland
| | - Anna Sarnowska
- Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, Warsaw, Poland.
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Luca A, Fonta C, Raffoul W, Summa P, Lacour S. In vitro evaluation of gel‐encapsulated adipose derived stem cells: Biochemical cues for in vivo peripheral nerve repair. J Tissue Eng Regen Med 2017; 12:676-686. [DOI: 10.1002/term.2486] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 05/15/2017] [Accepted: 05/19/2017] [Indexed: 12/13/2022]
Affiliation(s)
- A.C. Luca
- Bertarelli Foundation Chair in Neuroprosthetic Technology, Laboratory for Soft Bioelectronic Interfaces, Institute of Microengineering, Institute of Bioengineering, Centre for NeuroprostheticsÉcole Polytechnique Fédérale de Lausanne (EPFL) Lausanne Switzerland
| | - C.M. Fonta
- Bertarelli Foundation Chair in Neuroprosthetic Technology, Laboratory for Soft Bioelectronic Interfaces, Institute of Microengineering, Institute of Bioengineering, Centre for NeuroprostheticsÉcole Polytechnique Fédérale de Lausanne (EPFL) Lausanne Switzerland
| | - W. Raffoul
- Department of Plastic, Reconstructive and Hand SurgeryUniversity Hospital of Lausanne (CHUV) Lausanne Switzerland
| | - P.G. Summa
- Department of Plastic, Reconstructive and Hand SurgeryUniversity Hospital of Lausanne (CHUV) Lausanne Switzerland
| | - S.P. Lacour
- Bertarelli Foundation Chair in Neuroprosthetic Technology, Laboratory for Soft Bioelectronic Interfaces, Institute of Microengineering, Institute of Bioengineering, Centre for NeuroprostheticsÉcole Polytechnique Fédérale de Lausanne (EPFL) Lausanne Switzerland
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Yokoi T, Uemura T, Takamatsu K, Shintani K, Onode E, Okada M, Hidaka N, Nakamura H. Bioabsorbable nerve conduits coated with induced pluripotent stem cell-derived neurospheres enhance axonal regeneration in sciatic nerve defects in aged mice. J Biomed Mater Res B Appl Biomater 2017; 106:1752-1758. [PMID: 28888079 DOI: 10.1002/jbm.b.33983] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 05/16/2017] [Accepted: 08/16/2017] [Indexed: 11/10/2022]
Abstract
Aging influences peripheral nerve regeneration. Nevertheless, most basic research of bioabsorbable nerve conduits including commercial products have been performed in very young animals. Results from these studies may not provide information about axonal regeneration in aged tissue, because young nerve tissue holds sufficient endogenous potential for axonal regeneration. The clinical target age for nerve conduit application is most likely going to increase with a rapidly growing elderly population. In the present study, we examined axonal regeneration after sciatic nerve defects in aged and young mice. 5-mm sciatic nerve defects in young (6 weeks old) and aged (92 weeks old) mice were reconstructed using nerve conduits (composed of a poly lactide and caprolactone) or autografts. In addition, in aged mice, sciatic nerve defects were reconstructed using nerve conduits coated with mouse induced pluripotent stem cell (iPSc)-derived neurospheres. Using electrophysiological and histological techniques, we demonstrated axonal regeneration was significantly less effective in aged than in young mice both for nerve conduits and for nerve autografts. However, despite the low regenerative capacity of the peripheral nerve in aged mice, axonal regeneration significantly increased when nerve conduits coated with iPSc-derived neurospheres, rather than nerve conduits alone, were used. The present study shows that aging negatively affects peripheral nerve regeneration based on nerve conduits in mice. However, axonal regeneration using nerve conduits was improved when supportive iPSc-derived neurospheres were added in the aged mice. We propose that tissue-engineered bioabsorbable nerve conduits in combination with iPSc-derived neurospheres hold therapeutic potential both in young and elderly patients. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1752-1758, 2018.
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Affiliation(s)
- Takuya Yokoi
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Takuya Uemura
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kiyohito Takamatsu
- Department of Orthopaedic Surgery, Yodogawa Christian Hospital, Osaka, Japan
| | - Kosuke Shintani
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Ema Onode
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Mitsuhiro Okada
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Noriaki Hidaka
- Department of Orthopaedic Surgery, Osaka City General Hospital, Osaka, Japan
| | - Hiroaki Nakamura
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
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Repair of nerve injury by implanting prostheses obtained from isogenic acellular nerve segments. Rev Esp Cir Ortop Traumatol (Engl Ed) 2017. [DOI: 10.1016/j.recote.2017.08.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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García-Medrano B, Mesuro Domínguez N, Simón Pérez C, Garrosa García M, Gayoso Del Villar S, Mayo Íscar A, Gayoso Rodríguez MJ, Martín Ferrero MA. Repair of nerve injury by implanting prostheses obtained from isogenic acellular nerve segments. Rev Esp Cir Ortop Traumatol (Engl Ed) 2017; 61:359-366. [PMID: 28760548 DOI: 10.1016/j.recot.2017.06.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 05/22/2017] [Accepted: 06/09/2017] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION When a nerve section with a significant gap occurs, it is necessary to use a prosthesis to suture it. To date an autologous nerve segment graft appears to be the best treatment; but it has several important disadvantages. Our goal is to study the effectiveness of an isogenic acellular nerve prosthesis comparing a simple suture with tubulisation. MATERIAL AND METHOD Four groups of Wistar rats were used. The animals in Group 0 served as donors of nerve segments to graft. Group 1 received the implant with an end-to-end suture. In group 2, the implant was sutured inside an ɛ-caprolactone tube. Group 3 received it in a polylactic-co-glycolic acid tube. We evaluated the motor function (sciatic index and step test in motion), and the regeneration length by histological study of regeneration, after a maximum of 3 weeks. RESULTS Regeneration was uneven in the three groups. In all groups, there were implants with regenerated nerve fibres at the maximum studied length (15mm) and others where regeneration was scarce. The mean regeneration length was greater in the direct end-to-end suture group (G1), although the regeneration speed was similar in the three groups. Group 1 showed the highest percentage of regeneration, but the variability of results prevents this difference reaching statistical significance. We found no significant differences between the two groups with polymer tubes. CONCLUSION For the implantation of isogenic acellular nerve prosthesis, under our experimental conditions, the direct end-to-end suture was more effective than when it isprotected with biopolymer tubes.
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Affiliation(s)
- B García-Medrano
- Servicio de Cirugía Ortopédica y Traumatología, Hospital Clínico Universitario de Valladolid, Valladolid, España.
| | - N Mesuro Domínguez
- Departamento de Biología Celular, Facultad de Medicina, Universidad de Valladolid, Valladolid, España
| | - Cl Simón Pérez
- Servicio de Cirugía Ortopédica y Traumatología, Hospital Clínico Universitario de Valladolid, Valladolid, España
| | - M Garrosa García
- Estadística e Investigación Operativa, Universidad de Medicina de Valladolid, Valladolid, España
| | - S Gayoso Del Villar
- Departamento de Biología Celular, Facultad de Medicina, Universidad de Valladolid, Valladolid, España
| | - A Mayo Íscar
- Estadística e Investigación Operativa, Universidad de Medicina de Valladolid, Valladolid, España
| | - M J Gayoso Rodríguez
- Departamento de Biología Celular, Facultad de Medicina, Universidad de Valladolid, Valladolid, España
| | - M A Martín Ferrero
- Servicio de Cirugía Ortopédica y Traumatología, Hospital Clínico Universitario de Valladolid, Valladolid, España
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Naderi N, Combellack EJ, Griffin M, Sedaghati T, Javed M, Findlay MW, Wallace CG, Mosahebi A, Butler PEM, Seifalian AM, Whitaker IS. The regenerative role of adipose-derived stem cells (ADSC) in plastic and reconstructive surgery. Int Wound J 2017; 14:112-124. [PMID: 26833722 PMCID: PMC7949873 DOI: 10.1111/iwj.12569] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 11/24/2015] [Accepted: 12/01/2015] [Indexed: 12/12/2022] Open
Abstract
The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs offers a paradigm shift in plastic and reconstructive surgery. The use of either embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC) in clinical situations is limited because of regulations and ethical considerations even though these cells are theoretically highly beneficial. Adult mesenchymal stem cells appear to be an ideal stem cell population for practical regenerative medicine. Among these cells, adipose-derived stem cells (ADSC) have the potential to differentiate the mesenchymal, ectodermal and endodermal lineages and are easy to harvest. Additionally, adipose tissue yields a high number of ADSC per volume of tissue. Based on this background knowledge, the purpose of this review is to summarise and describe the proliferation and differentiation capacities of ADSC together with current preclinical data regarding the use of ADSC as regenerative tools in plastic and reconstructive surgery.
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Affiliation(s)
- Naghmeh Naderi
- Reconstructive Surgery & Regenerative Medicine Group, Institute of Life Sciences (ILS)Swansea University Medical SchoolSwanseaUK
- Welsh Centre for Burns & Plastic SurgeryABMU Health BoardSwanseaUK
| | - Emman J Combellack
- Reconstructive Surgery & Regenerative Medicine Group, Institute of Life Sciences (ILS)Swansea University Medical SchoolSwanseaUK
- Welsh Centre for Burns & Plastic SurgeryABMU Health BoardSwanseaUK
| | - Michelle Griffin
- UCL Centre for Nanotechnology and Regenerative MedicineUniversity College LondonLondonUK
| | - Tina Sedaghati
- UCL Centre for Nanotechnology and Regenerative MedicineUniversity College LondonLondonUK
| | - Muhammad Javed
- Reconstructive Surgery & Regenerative Medicine Group, Institute of Life Sciences (ILS)Swansea University Medical SchoolSwanseaUK
- Welsh Centre for Burns & Plastic SurgeryABMU Health BoardSwanseaUK
| | - Michael W Findlay
- Plastic & Reconstructive SurgeryStanford University Medical CentreStanfordCAUSA
| | | | - Afshin Mosahebi
- UCL Centre for Nanotechnology and Regenerative MedicineUniversity College LondonLondonUK
- Department of Plastic SurgeryRoyal Free NHS Foundation TrustLondonUK
| | - Peter EM Butler
- Department of Plastic SurgeryRoyal Free NHS Foundation TrustLondonUK
| | - Alexander M Seifalian
- UCL Centre for Nanotechnology and Regenerative MedicineUniversity College LondonLondonUK
| | - Iain S Whitaker
- Reconstructive Surgery & Regenerative Medicine Group, Institute of Life Sciences (ILS)Swansea University Medical SchoolSwanseaUK
- Welsh Centre for Burns & Plastic SurgeryABMU Health BoardSwanseaUK
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Rafee MA, Amarpal, Kinjavdekar P, Aithal HP, Wani SA, Bhat IA. Guinea pigs as an animal model for sciatic nerve injury. Neural Regen Res 2017; 12:452-457. [PMID: 28469661 PMCID: PMC5399724 DOI: 10.4103/1673-5374.202929] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The overwhelming use of rat models in nerve regeneration studies is likely to induce skewness in treatment outcomes. To address the problem, this study was conducted in 8 adult guinea pigs of either sex to investigate the suitability of guinea pig as an alternative model for nerve regeneration studies. A crush injury was inflicted to the sciatic nerve of the left limb, which led to significant decrease in the pain perception and neurorecovery up to the 4th weak. Lengthening of foot print and shortening of toe spread were observed in the paw after nerve injury. A 3.49 ± 0.35 fold increase in expression of neuropilin 1 (NRP1) gene and 2.09 ± 0.51 fold increase in neuropilin 2 (NRP2) gene were recorded 1 week after nerve injury as compared to the normal nerve. Ratios of gastrocnemius muscle weight and volume of the experimental limb to control limb showed more than 50% decrease on the 30th day. Histopathologically, vacuolated appearance of the nerve was observed with presence of degenerated myelin debris in digestion chambers. Gastrocnemius muscle also showed degenerative changes. Scanning electron microscopy revealed loose and rough arrangement of connective tissue fibrils and presence of large spherical globules in crushed sciatic nerve. The findings suggest that guinea pigs could be used as an alternative animal model for nerve regeneration studies and might be preferred over rats due to their cooperative nature while recording different parameters.
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Affiliation(s)
- Malik Abu Rafee
- Division of Surgery, Indian Veterinary Research Institute, Izatnagar, Bareilly, UP, India
| | - Amarpal
- Division of Surgery, Indian Veterinary Research Institute, Izatnagar, Bareilly, UP, India
| | - Prakash Kinjavdekar
- Division of Surgery, Indian Veterinary Research Institute, Izatnagar, Bareilly, UP, India
| | - Hari Prasad Aithal
- Division of Surgery, Indian Veterinary Research Institute, Izatnagar, Bareilly, UP, India
| | - Sajad Ahmad Wani
- Division of Veterinary Biotechnology, Indian Veterinary Research Institute, Izatnagar, Bareilly, UP, India
| | - Irfan Ahmad Bhat
- Division of Veterinary Physiology, Indian Veterinary Research Institute, Izatnagar, Bareilly, UP, India
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Hu Y, Wu Y, Gou Z, Tao J, Zhang J, Liu Q, Kang T, Jiang S, Huang S, He J, Chen S, Du Y, Gou M. 3D-engineering of Cellularized Conduits for Peripheral Nerve Regeneration. Sci Rep 2016; 6:32184. [PMID: 27572698 PMCID: PMC5004136 DOI: 10.1038/srep32184] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 08/02/2016] [Indexed: 02/05/2023] Open
Abstract
Tissue engineered conduits have great promise for bridging peripheral nerve defects by providing physical guiding and biological cues. A flexible method for integrating support cells into a conduit with desired architectures is wanted. Here, a 3D-printing technology is adopted to prepare a bio-conduit with designer structures for peripheral nerve regeneration. This bio-conduit is consisted of a cryopolymerized gelatin methacryloyl (cryoGelMA) gel cellularized with adipose-derived stem cells (ASCs). By modeling using 3D-printed “lock and key” moulds, the cryoGelMA gel is structured into conduits with different geometries, such as the designed multichannel or bifurcating and the personalized structures. The cryoGelMA conduit is degradable and could be completely degraded in 2-4 months in vivo. The cryoGelMA scaffold supports the attachment, proliferation and survival of the seeded ASCs, and up-regulates the expression of their neurotrophic factors mRNA in vitro. After implanted in a rat model, the bio-conduit is capable of supporting the re-innervation across a 10 mm sciatic nerve gap, with results close to that of the autografts in terms of functional and histological assessments. The study describes an indirect 3D-printing technology for fabricating cellularized designer conduits for peripheral nerve regeneration, and could lead to the development of future nerve bio-conduits for clinical use.
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Affiliation(s)
- Yu Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan province, China.,Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan province, China
| | - Yao Wu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan province, China
| | - Zhiyuan Gou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan province, China
| | - Jie Tao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan province, China
| | - Jiumeng Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan province, China
| | - Qianqi Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan province, China
| | - Tianyi Kang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan province, China
| | - Shu Jiang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan province, China
| | - Siqing Huang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan province, China
| | - Jiankang He
- State key laboratory for manufacturing systems engineering, Xi'an Jiaotong University, Xi'an, 710049,China
| | - Shaochen Chen
- Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, USA
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084. China
| | - Maling Gou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan province, China
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Peripheral Motor and Sensory Nerve Conduction following Transplantation of Undifferentiated Autologous Adipose Tissue–Derived Stem Cells in a Biodegradable U.S. Food and Drug Administration–Approved Nerve Conduit. Plast Reconstr Surg 2016; 138:132-139. [DOI: 10.1097/prs.0000000000002291] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Adipose-Derived Stem Cells Promote Peripheral Nerve Regeneration In Vivo without Differentiation into Schwann-Like Lineage. Plast Reconstr Surg 2016; 137:318e-330e. [PMID: 26818322 DOI: 10.1097/01.prs.0000475762.86580.36] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND During recent decades, multipotent stem cells were found to reside in the adipose tissue, and these adipose-derived stem cells were shown to play beneficial roles, like those of Schwann cells, in peripheral nerve regeneration. However, it has not been well established whether adipose-derived stem cells offer beneficial effects to peripheral nerve injuries in vivo as Schwann cells do. Furthermore, the in situ survival and differentiation of adipose-derived stem cells after transplantation at the injured peripheral nerve tissue remain to be fully elucidated. METHODS Adipose-derived stem cells and Schwann cells were transplanted with gelatin hydrogel tubes at the artificially blunted sciatic nerve lesion in mice. Neuroregenerative abilities of them were comparably estimated. Cre-loxP-mediated fate tracking was performed to visualize survival in vivo of transplanted adipose-derived stem cells and to investigate whether they differentiated into Schwann linage cells at the peripheral nerve injury site. RESULTS The transplantation of adipose-derived stem cells promoted regeneration of axons, formation of myelin, and restoration of denervation muscle atrophy to levels comparable to those achieved by Schwann cell transplantation. The adipose-derived stem cells survived for at least 4 weeks after transplantation without differentiating into Schwann cells. CONCLUSIONS Transplanted adipose-derived stem cells did not differentiate into Schwann cells but promoted peripheral nerve regeneration at the injured site. The neuroregenerative ability was comparable to that of Schwann cells. Adipose-derived stem cells at an undifferentiated stage may be used as an alternative cell source for autologous cell therapy for patients with peripheral nerve injury.
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