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hESC-derived neural progenitors prevent xenograft rejection through neonatal desensitisation.

Heuer A, Kirkeby A, Pfisterer U, Jönsson ME, Parmar M - Exp. Neurol. (2016)

Bottom Line: Neonatal injections in rat pups using human fetal brain cells have been shown to desensitise the host to accept human tissue grafts as adults, whilst not compromising their immune system.Here, we show that differentiated human embryonic stem cells (hESCs) can be used for desensitisation to achieve long-term graft survival of human stem cell-derived neurons in a xenograft setting, surpassing the time of conventional pharmacological immune-suppressive treatments.The use of hESCs for desensitisation opens up for a widespread use of the technique, which will be of great value when performing pre-clinical evaluation of stem cell-derived neurons in animal models.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden.

No MeSH data available.


Related in: MedlinePlus

H9 hESC-derived cells desensitise the host to other hESC lines.Graft survival of (A) CsA immune-suppressed (CsA H9; n = 8 + 3), (B) identical (Des H9; n = 8 + 2, H9 to H9-desensitised) and (C) different (Des RC17; n = 8 + 4, RC17 to H9-desensitised) hESC donor – host combinations. (E) A subset of animals was sacrificed after 6 weeks. The percentage of survival was similar in all groups 18 weeks post-transplantation (E, n = 8 per group). Graft sizes were different between the three groups, with RC17 transplants being significantly larger, whilst the graft areas were similar for H9 grafts in CsA or desensitised hosts. Grafts of H9 hESC origin into naïve animals were readily rejected within 6 weeks post transplantation (D; see also Fig. 3). Scalebar = 100 μM. All data in E are presented as mean ± SEM.
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f0010: H9 hESC-derived cells desensitise the host to other hESC lines.Graft survival of (A) CsA immune-suppressed (CsA H9; n = 8 + 3), (B) identical (Des H9; n = 8 + 2, H9 to H9-desensitised) and (C) different (Des RC17; n = 8 + 4, RC17 to H9-desensitised) hESC donor – host combinations. (E) A subset of animals was sacrificed after 6 weeks. The percentage of survival was similar in all groups 18 weeks post-transplantation (E, n = 8 per group). Graft sizes were different between the three groups, with RC17 transplants being significantly larger, whilst the graft areas were similar for H9 grafts in CsA or desensitised hosts. Grafts of H9 hESC origin into naïve animals were readily rejected within 6 weeks post transplantation (D; see also Fig. 3). Scalebar = 100 μM. All data in E are presented as mean ± SEM.

Mentions: When analysing the grafts after 18–24 weeks, we found that neonatal desensitisation resulted in long-term graft survival in both desensitised groups as well as in the CsA control group (CsA H9; n = 8) to a similar extent (Fig. 2, A–C, E–F). When assessing graft sizes (Fig. 2, E) we found a significant difference between the three transplant groups (Group, F2,12 = 8.87, p < 0.01). Post-hoc assessment (Bonferroni corrected α) revealed that the difference was due to the cell line used (Des RC17 > Des H9 and Des RC17 > CsA H9, both: p < 0.05) whereas the grafts from the H9-donor cells were of similar size, irrespective of immunosuppression regime applied (Des = CsA, p = n.s.). When comparing the RC17 graft survival and appearance with other experiments where we use CsA or nude rats for immunosuppression (Supplementary Fig. 1), we did not see a major difference to the experiments in this study where we use H9 desensitised rats as hosts, and therefore we ascribe this difference in graft size to differences in the cell line, rather than differences in the host response.


hESC-derived neural progenitors prevent xenograft rejection through neonatal desensitisation.

Heuer A, Kirkeby A, Pfisterer U, Jönsson ME, Parmar M - Exp. Neurol. (2016)

H9 hESC-derived cells desensitise the host to other hESC lines.Graft survival of (A) CsA immune-suppressed (CsA H9; n = 8 + 3), (B) identical (Des H9; n = 8 + 2, H9 to H9-desensitised) and (C) different (Des RC17; n = 8 + 4, RC17 to H9-desensitised) hESC donor – host combinations. (E) A subset of animals was sacrificed after 6 weeks. The percentage of survival was similar in all groups 18 weeks post-transplantation (E, n = 8 per group). Graft sizes were different between the three groups, with RC17 transplants being significantly larger, whilst the graft areas were similar for H9 grafts in CsA or desensitised hosts. Grafts of H9 hESC origin into naïve animals were readily rejected within 6 weeks post transplantation (D; see also Fig. 3). Scalebar = 100 μM. All data in E are presented as mean ± SEM.
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f0010: H9 hESC-derived cells desensitise the host to other hESC lines.Graft survival of (A) CsA immune-suppressed (CsA H9; n = 8 + 3), (B) identical (Des H9; n = 8 + 2, H9 to H9-desensitised) and (C) different (Des RC17; n = 8 + 4, RC17 to H9-desensitised) hESC donor – host combinations. (E) A subset of animals was sacrificed after 6 weeks. The percentage of survival was similar in all groups 18 weeks post-transplantation (E, n = 8 per group). Graft sizes were different between the three groups, with RC17 transplants being significantly larger, whilst the graft areas were similar for H9 grafts in CsA or desensitised hosts. Grafts of H9 hESC origin into naïve animals were readily rejected within 6 weeks post transplantation (D; see also Fig. 3). Scalebar = 100 μM. All data in E are presented as mean ± SEM.
Mentions: When analysing the grafts after 18–24 weeks, we found that neonatal desensitisation resulted in long-term graft survival in both desensitised groups as well as in the CsA control group (CsA H9; n = 8) to a similar extent (Fig. 2, A–C, E–F). When assessing graft sizes (Fig. 2, E) we found a significant difference between the three transplant groups (Group, F2,12 = 8.87, p < 0.01). Post-hoc assessment (Bonferroni corrected α) revealed that the difference was due to the cell line used (Des RC17 > Des H9 and Des RC17 > CsA H9, both: p < 0.05) whereas the grafts from the H9-donor cells were of similar size, irrespective of immunosuppression regime applied (Des = CsA, p = n.s.). When comparing the RC17 graft survival and appearance with other experiments where we use CsA or nude rats for immunosuppression (Supplementary Fig. 1), we did not see a major difference to the experiments in this study where we use H9 desensitised rats as hosts, and therefore we ascribe this difference in graft size to differences in the cell line, rather than differences in the host response.

Bottom Line: Neonatal injections in rat pups using human fetal brain cells have been shown to desensitise the host to accept human tissue grafts as adults, whilst not compromising their immune system.Here, we show that differentiated human embryonic stem cells (hESCs) can be used for desensitisation to achieve long-term graft survival of human stem cell-derived neurons in a xenograft setting, surpassing the time of conventional pharmacological immune-suppressive treatments.The use of hESCs for desensitisation opens up for a widespread use of the technique, which will be of great value when performing pre-clinical evaluation of stem cell-derived neurons in animal models.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden.

No MeSH data available.


Related in: MedlinePlus