Stem cell therapy

Stem cell therapy mainly uses natural stem cells for transplantation, and the use of genetic engineering to optimize stem cell products is a very important process. This article reviews successful gene modification methods in the field of immune cell therapy and summarizes some attempts at stem cell gene editing in current research. Cell bridging is an innovative cutting-edge strategy that includes the specific recognition and signal transduction of artificial receptors. The “off-the-shelf” cell strategies mainly introduce the advantages of allogeneic cell therapy and how to overcome issues such as immunogenicity. Gene regulatory systems allow us to manipulate cells with small molecules to control cellular phenotypes. In addition, we also summarize some important genes that can provide a reference for cell genetic engineering. In conclusion, we summarize a variety of technical strategies for gene editing cells to provide useful ideas and experiences for future stem cell therapy research 1).

Regenerative therapy using stem cell technologies have been developed for various neurological diseases. Although stem cell therapy is an attractive option to reverse neural tissue damage and to recover neurological deficits, it is still under development so as not to show significant treatment effects in clinical settings.

see neural stem cell.

A clinical trial involving 12 patients with complete and chronic paraplegia (average time of chronicity, 13.86 years; SD, 9.36). The characteristics of spinal cord injury SCI in magnetic resonance imaging (MRI) were evaluated for a personalized local administration of expanded autologous bone marrow mesenchymal stromal cells (MSCs) supported in autologous plasma, with the number of MSCs ranging from 100 × 106 to 230 × 106. An additional 30 × 106 MSCs were administered 1 month later by lumbar puncture into the subarachnoid space. Outcomes were evaluated at 3, 6, 9 and 12 months after surgery through clinical, urodynamic, neurophysiological and neuroimaging studies.

Cell transplantation is a safe procedure. All patients experienced improvement, primarily in sensitivity and sphincter control. Infralesional motor activity, according to clinical and neurophysiological studies, was obtained by more than 50% of the patients. Decreases in spasms and spasticity, and improved sexual function were also common findings. Clinical improvement seems to be dose-dependent but was not influenced by the chronicity of the SCI.

Personalized cell therapy with MSCs is safe and leads to clear improvements in clinical aspects and quality of life for patients with complete and chronically established paraplegia 2).

A 18-year-old woman who sustained a complete spinal cord injury at T10-11. Three years after injury, she remained with paraplegia and underwent olfactory mucosal cell implantation at the site of injury. She developed back pain 8 years later, and imaging revealed an Intramedullary spinal cord tumor at the site of cell implantation, which required resection. Intraoperative findings revealed an expanded spinal cord with a multicystic mass containing large amounts of thick mucus-like material. Histological examination and immunohistochemical staining revealed that the mass was composed mostly of cysts lined by respiratory epithelium, submucosal glands with goblet cells, and intervening nerve twigs. This is the first report of a human spinal cord mass complicating spinal cord cell transplantation and neural stem cell therapy. Given the prolonged time to presentation, safety monitoring of all patients with cell transplantation and neural stem cell implantation should be maintained for many years 3).

Neonatal OECs were implanted in the striatum after a 6-hydroxydopamine lesion of the ipsilateral substantia nigra. Amphetamine-induced rotational asymmetry scores were determined 48 hours before and 4, 6 and 8 weeks after OEC implantation. The density of immunostaining for tyrosine hydroxylase and synaptophysin in the striatum and the number of tyrosine hydroxylase-positive cells remaining in the substantia nigra were also determined. RESULTS: Rotational asymmetry scores were similar in OEC-implanted and vehicle-treated groups at all time points examined, and at each time were similar to those observed prior to implantation. Levels of striatal tyrosine-hydroxylase and synaptophysin immunoreactivity were similar in OEC- and vehicle-treated groups. The number of tyrosine-hydroxylase-positive cells in the substantia nigra was similar in both groups indicating that severity of the lesion was similar. Visualisation of GFP-labelled OECs one week after implantation in a separate group of animals revealed the cells to be located in the area immediately surrounding the needle tract. CONCLUSION: This study demonstrates that implantation of OECs alone is not sufficient to promote tissue repair and functional recovery in a rodent model of parkinsonism. The results add to a growing number of studies that propose a caveat for the use of pure OECs as a neurosurgical strategy for the treatment of brain disease or injury 4).

Cell-based regenerative approaches have been suggested as primary or adjuvant procedures for the treatment of intervertebral disc degeneration.

Tissue from the Nucleus pulposus compartment of 10 patients with mild or severe grades of intervertebral disc degeneration (IVD) was collected. Cells were isolated, expanded with and without basic fibroblast growth factor and cultured in 3D fibrin/poly (lactic-co-glycolic) acid transplants for 21 days. Real-time reverse-transcription polymerase chain reaction (RT-PCR) showed the expression of characteristic NP markers ACAN, COL1A1 and COL2A1 in 2D- and 3D-culture with degeneration- and culture-dependent differences. In a 5,6-carboxyfluorescein diacetate N-succinimidyl ester-based proliferation assay, NP cells in monolayer, regardless of their grade of degeneration, did not provoke a significant proliferation response in T cells, natural killer (NK) cells or B cells, not only with donor PBMC, but also with allogeneic PBMC. In conjunction with low inflammatory cytokine expression, analyzed by Cytometric Bead Array and fluorescence-activated cell sorting (FACS), a low immunogenicity can be assumed, facilitating possible therapeutic approaches. In 3D-culture, however, we found elevated immune cell proliferation levels, and there was a general trend to higher responses for NP cells from severely degenerated IVD tissue. This emphasizes the importance of considering the specific immunological alterations when including biomaterials in a therapeutic concept. The overall expression of Fas receptor, found on cultured NP cells, could have disadvantageous implications on their potential therapeutic applications because they could be the targets of cytotoxic T-cell activity acting by Fas ligand-induced apoptosis 5).

Cell therapy in neurological disability after traumatic brain injury (TBI) is in its initial clinical stage.

Vaquero et al., describe the preliminary clinical experience with three patients with diffuse axonal injury (DAI) who were treated with intrathecal administration of autologous mesenchymal stromal cells (MSCs).

Three patients with established neurological sequelae due to DAI received intrathecally autologous MSCs. The total number of MSCs administered was 60 × 106 (one patient), 100 × 106 (one patient) and 300 × 106 (one patient).

All three patients showed improvement after cell therapy, and subsequent studies with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) showed a diffuse and progressive increase in brain glucose metabolism.

The present results suggest benefit of intrathecal administration of MSCs in patients with DAI, as well as a relationship between this type of treatment and increase in brain glucose metabolism. These preliminary findings raise the question of convenience of assessing the potential benefit of intrathecal administration of MSCs for brain diseases in which a decrease in glucose metabolism represents a crucial pathophysiological finding, such as Alzheimer's disease (AD) and other dementias 6).

Li S, Tang H, Li C, Ma J, Ali M, Dong Q, Wu J, Hui Y, Sun C. Synthetic Biology Technologies And Genetically Engineering Strategies For Enhanced Cell Therapeutics. Stem Cell Rev Rep. 2022 Sep 27. doi: 10.1007/s12015-022-10454-5. Epub ahead of print. PMID: 36166137.
Vaquero J, Zurita M, Rico MA, Bonilla C, Aguayo C, Montilla J, Bustamante S, Carballido J, Marin E, Martinez F, Parajon A, Fernandez C, Reina L; Neurological Cell Therapy Group. An approach to personalized cell therapy in chronic complete paraplegia: The Puerta de Hierro phase I/II clinical trial. Cytotherapy. 2016 Jun 13. pii: S1465-3249(16)30377-2. doi: 10.1016/j.jcyt.2016.05.003. [Epub ahead of print] PubMed PMID: 27311799.
Dlouhy BJ, Awe O, Rao RC, Kirby PA, Hitchon PW. Autograft-derived spinal cord mass following olfactory mucosal cell transplantation in a spinal cord injury patient. J Neurosurg Spine. 2014 Oct;21(4):618-22. doi: 10.3171/2014.5.SPINE13992. Epub 2014 Jul 8. PubMed PMID: 25002238.
Dewar D, Bentley D, Barnett SC. Implantation of pure cultured olfactory ensheathing cells in an animal model of parkinsonism. Acta Neurochir (Wien). 2007;149(4):407-14. Epub 2007 Mar 28. PubMed PMID: 17380250.
Stich S, Stolk M, Girod PP, Thomé C, Sittinger M, Ringe J, Seifert M, Hegewald AA. Regenerative and Immunogenic Characteristics of Cultured Nucleus Pulposus Cells from Human Cervical Intervertebral Discs. PLoS One. 2015 May 19;10(5):e0126954. doi: 10.1371/journal.pone.0126954. eCollection 2015. PubMed PMID: 25993467.
Vaquero J, Zurita M, Bonilla C, Fernández C, Rubio JJ, Mucientes J, Rodriguez B, Blanco E, Donis L. Progressive increase in brain glucose metabolism after intrathecal administration of autologous mesenchymal stromal cells in patients with diffuse axonal injury. Cytotherapy. 2016 Nov 2. pii: S1465-3249(16)30546-1. doi: 10.1016/j.jcyt.2016.10.001. [Epub ahead of print] PubMed PMID: 27816409.
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