Table 2.
Safety, efficacy, scalability, and quality control considerations for clinical application of NSC from different sources.
| Origin | Type of NSC | Safety | Efficacy | Immunogenicity | Ethical Concerns | Procurement | Logistics/Scalability | References |
|---|---|---|---|---|---|---|---|---|
| CNS | fNSC | Safe as confirmed by multiple clinical trials and animal models | Some clinical studies describe positive results but none demonstrating sustained recovery | Immunosuppression required (only allogeneic setting is feasible). | Derived from human fetuses, usually from elected abortions | Difficult. Ethical concerns complicate procurement being forbidden in some countries | Easy. Once obtained, cells are easy to grow and scale-up | [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,42,50,108] |
| Gz-NSC | Only confirmed in animal models | Not confirmed | No Immunosuppression required in autologous settings. High HLA expression can impede their allogenic use | No ethical issues as the original source (CSF of IVH preterm infants) is usually discarded and do not imply an extra surgery in the patient | Difficult. Few IVH cases and not all hospitals perform therapeutic neuroendoscopies to remove CSF in IVH patients. | Easy. Once obtained cells are easy to grow and scale-up. Autologous setting is costly and allogenic setting not possible due to the high HLA expression | [4] | |
| NTD-NSC | Only confirmed in animal models | Only confirmed in animal models | No Immunosuppression required in autologous settings. Immunosuppression required in allogenic treatments. | No ethical issues as the original source (CSF of NTD patients) is usually discarded and do not imply an extra surgery in the patient | Difficult. Few NTD cases | Easy. Cells are easy to grow and scale-up | [5,6,7,51] | |
| NSC from adult biopsies/autopsies | Safety confirmed in animal models and few clinical cases | Efficacy confirmed in animal models and few clinical cases | No Immunosuppression required in autologous settings. Immunosuppression required in allogenic treatments. | Biopsy procurement potentially risky for the patient | Difficult. Few cells in the source | Difficult. Few cells with probably lower growth capabilities. | [54,55,56,57,58] | |
| PSC | iPSC-NSC | Only confirmed in animal models. Safety concerns related to the use of exogenous transcription factors, the enrichment of somatic mutations, and the fact that epigenetic marks from the original somatic cell are not totally erased. Turmorigenic risk due to potential PSC residues. | Only confirmed in animal models | No Immunosuppression required in autologous settings. Immunosuppression required in allogenic treatments. | Invasive surgery in some cases to obtain the initial cell type used for reprogramming (e.g., skin fibroblast isolation) | Easy. The initial cell type used for reprogramming is usually easily accessible e.g., coming from a skin biopsy or blood sample | Easy. Establishment of iPSC lines is time-consuming and requires trained operators but once the PSC cells are obtained they are easy to grow, allowing safe production of many cell doses. | [60,61,62,64,65,66,67,68,71,74,95] |
| ESC-NSC | Only confirmed in animal models. Turmorigenic risk due to potential PSC residues. | Only confirmed in animal models | Immunosuppression required (only allogeneic setting is feasible). | Derived from human embryos | Difficult. Ethical concerns complicate procurement being forbidden in some countries | Easy. Establishment of ESC lines is time-consuming and requires trained operators but once the PSC cells are obtained they are easy to grow, allowing safe production of many cell doses. | [60,69,70,72,73,101,102] | |
| pESC-NSC | Only confirmed in animal models. Turmorigenic risk due to potential PSC residues. Haploid cells | Only confirmed in animal models | Immunosuppression required (only allogeneic setting is feasible). | Derived from human oocytes (ethical concerns about the payment to oocyte donors, the medical risks of oocyte retrieval, and with the affectation of their reproduction success as this can be compromised because fewer oocytes are available for reproductive purposes) | Difficult. Ethical concerns complicate procurement. | Easy. Establishment of pESC lines is time-consuming and requires trained operators but once the PSC cells are obtained they are easy to grow, allowing safe production of many cell doses. | [75,109] | |
| ntESC-NSC | Only confirmed in animal models. Turmorigenic risk due to potential PSC residues | Only confirmed in animal models | Immunosuppression required (only allogeneic setting is feasible). | Derived from human oocytes (ethical concerns about the payment to oocyte donors, the medical risks of oocyte retrieval, and with the affectation of their reproduction success as this can be compromised because fewer oocytes are available for reproductive purposes) | Difficult. Ethical concerns complicate procurement. | Easy. Establishment of ntESC lines is time consuming and requires trained operators but once the PSC cells are obtained they are easy to grow, allowing safe production of many cell doses. | [110] | |
| Direct reprogramming | iNSC | Only confirmed in animal models. Safety concerns related to the use of exogenous transcription factors and the fact that epigenetic marks from the original somatic cell are not erased. | Only confirmed in animal models | No immunosuppression required in autologous settings. Immunosuppression required in allogenic treatments. | Invasive surgery in some cases to obtain the initial cell type used for reprogramming (e.g., skin fibroblast isolation) | Easy. The initial cell type used for reprogramming is usually easily accessible e.g., coming from a skin biopsy or blood sample | Easy. Establishment of iNSC lines is time-consuming but, once the iNSC are obtained, they are normally easy to grow, allowing safe production of many cell doses. | [80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,96,97,98,99] |
CNS: central nervous system. fNSC: fetal neural stem cells, Gz-NSC: germinal zone neural stem cells; NTD: neural tube defects; iNSC: induced neural stem cells; iPSC: induced pluripotent stem cells; ESC: embryonic stem cells; pESC: parthenogenetic stem cells; ntESC: nuclear transfer embryonic stem cells; IVH: intraventricular hemorrhage; CSF: cerebrospinal fluid; HLA: human leukocyte antigen.