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Background: Placenta-derived mesenchymal stem cells (PD-MSCs) have been highlighted as an alternative cell therapy agent that has become a next-generation stem cell treatment. Phosphatase of regenerating liver-1 (PRL-1), an immediate early gene, plays a critical role during liver regeneration. Here, we generated enhanced PRL-1 in PD-MSCs (PD-MSCsPRL-1, PRL-1+) using lentiviral and nonviral gene delivery systems and investigated mitochondrial functions by PD-MSCPRL-1 transplantation for hepatic functions in a rat bile duct ligation (BDL) model.
Methods: PD-MSCsPRL-1 were generated by lentiviral and nonviral AMAXA gene delivery systems and analyzed for their characteristics and mitochondrial metabolic functions. Liver cirrhosis was induced in Sprague-Dawley (SD) rats using common BDL for 10 days. PKH67+ naïve and PD-MSCsPRL-1 were intravenously administered into cirrhotic rats using a nonviral system (2x106 cells/animal). The animals were sacrificed at 1, 2, 3, and 5 weeks after transplantation and engraftment of stem cells, and histopathological analysis and hepatic mitochondrial functions were performed.
Results: PD-MSCsPRL-1 were successfully generated using lentiviral and nonviral AMAXA systems and maintained characteristics similar to those of naïve cells. Compared with naïve cells, PD-MSCsPRL-1 improved respirational metabolic states of mitochondria. In particular, mitochondria in PD-MSCsPRL-1 generated by the nonviral AMAXA system showed a significant increase in the respirational metabolic state, including ATP production and mitochondrial biogenesis (*p<0.05). Furthermore, transplantation of PD-MSCsPRL-1 using a nonviral AMAXA system promoted engraftment into injured target liver tissues of a rat BDL cirrhotic model and enhanced the metabolism of mitochondria via increased mtDNA and ATP production, thereby improving therapeutic efficacy.
Conclusions: Our findings will further our understanding of the therapeutic mechanism of enhanced MSCs and provide useful data for the development of next-generation MSC-based cell therapy and therapeutic strategies for regenerative medicine in liver disease.
Keywords
Chronic liver fibrosis, Mitochondria, Phosphatase of regenerating liver-1, Placenta-derived mesenchymal stem cells
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- revisedSupplementaryFigure1Kimetal.tif
Supplementary Fig. 1 Quantification of mitochondrial metabolism-specific genes in naïve and PD-MSCsPRL-1 using both gene delivery systems. Data from each group are shown as the mean ± SD. *p < 0.05 versus naïve; #p < 0.05 versus lenti. COX10; cytochrome c oxidase 10, Cyt c; cytochrome c, GAPDH; glyceraldehyde 3-phosphate dehydrogenase, HSP60; heat shock protein 60, PDH; pyruvate dehydrogenase, PHB1; prohibitin 1, SDHA; succinate dehydrogenase, SOD1; superoxide dismutase 1, VDAC; voltage-dependent anion channel
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CURRENT STATUS: Published
View the published article at Stem Cell Research & Therapy.
Version 3
Posted 17 Sep, 2020
No community comments so far
Editorial decision: Accept
On 13 Nov, 2020
Reviewer #1 agreed
On 21 Sep, 2020
Review #1 received
Received 21 Sep, 2020
Reviewers invited
Invitations sent on 20 Sep, 2020
Editor assigned
On 11 Sep, 2020
Submission checks complete
On 10 Sep, 2020
Editor invited
On 10 Sep, 2020
No comments provided
Editorial decision: Minor Revision
On 13 Aug, 2020
Review #1 received
Received 01 Jul, 2020
Reviewer #1 agreed
On 30 Jun, 2020
Reviewers invited
Invitations sent on 27 Jun, 2020
Editor assigned
On 18 Jun, 2020
Submission checks complete
On 17 Jun, 2020
Editor invited
On 17 Jun, 2020
No comments provided
Editorial decision: Major Revision
On 23 May, 2020
Review #4 received
Received 12 May, 2020
Review #2 received
Received 11 May, 2020
Review #1 received
Received 06 May, 2020
Review #3 received
Received 04 May, 2020
Reviewer #3 agreed
On 27 Apr, 2020
Reviewer #4 agreed
On 27 Apr, 2020
Reviewers invited
Invitations sent on 26 Apr, 2020
Reviewer #1 agreed
On 26 Apr, 2020
Reviewer #2 agreed
On 26 Apr, 2020
Editor assigned
On 16 Apr, 2020
Editor invited
On 15 Apr, 2020
Submission checks complete
On 14 Apr, 2020
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Subject Areas
Stem Cell & Developmental Cell Biology
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See the published version of this preprint at Stem Cell Research & Therapy.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Stem Cell Research & Therapy.
Version 3
Posted 17 Sep, 2020
No community comments so far
Editorial decision: Accept
On 13 Nov, 2020
Reviewer #1 agreed
On 21 Sep, 2020
Review #1 received
Received 21 Sep, 2020
Reviewers invited
Invitations sent on 20 Sep, 2020
Editor assigned
On 11 Sep, 2020
Submission checks complete
On 10 Sep, 2020
Editor invited
On 10 Sep, 2020
No comments provided
Editorial decision: Minor Revision
On 13 Aug, 2020
Review #1 received
Received 01 Jul, 2020
Reviewer #1 agreed
On 30 Jun, 2020
Reviewers invited
Invitations sent on 27 Jun, 2020
Editor assigned
On 18 Jun, 2020
Submission checks complete
On 17 Jun, 2020
Editor invited
On 17 Jun, 2020
No comments provided
Editorial decision: Major Revision
On 23 May, 2020
Review #4 received
Received 12 May, 2020
Review #2 received
Received 11 May, 2020
Review #1 received
Received 06 May, 2020
Review #3 received
Received 04 May, 2020
Reviewer #3 agreed
On 27 Apr, 2020
Reviewer #4 agreed
On 27 Apr, 2020
Reviewers invited
Invitations sent on 26 Apr, 2020
Reviewer #1 agreed
On 26 Apr, 2020
Reviewer #2 agreed
On 26 Apr, 2020
Editor assigned
On 16 Apr, 2020
Editor invited
On 15 Apr, 2020
Submission checks complete
On 14 Apr, 2020
First submitted
On 10 Apr, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Stem Cell & Developmental Cell Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Stem Cell Research & Therapy.
Background: Placenta-derived mesenchymal stem cells (PD-MSCs) have been highlighted as an alternative cell therapy agent that has become a next-generation stem cell treatment. Phosphatase of regenerating liver-1 (PRL-1), an immediate early gene, plays a critical role during liver regeneration. Here, we generated enhanced PRL-1 in PD-MSCs (PD-MSCsPRL-1, PRL-1+) using lentiviral and nonviral gene delivery systems and investigated mitochondrial functions by PD-MSCPRL-1 transplantation for hepatic functions in a rat bile duct ligation (BDL) model.
Methods: PD-MSCsPRL-1 were generated by lentiviral and nonviral AMAXA gene delivery systems and analyzed for their characteristics and mitochondrial metabolic functions. Liver cirrhosis was induced in Sprague-Dawley (SD) rats using common BDL for 10 days. PKH67+ naïve and PD-MSCsPRL-1 were intravenously administered into cirrhotic rats using a nonviral system (2x106 cells/animal). The animals were sacrificed at 1, 2, 3, and 5 weeks after transplantation and engraftment of stem cells, and histopathological analysis and hepatic mitochondrial functions were performed.
Results: PD-MSCsPRL-1 were successfully generated using lentiviral and nonviral AMAXA systems and maintained characteristics similar to those of naïve cells. Compared with naïve cells, PD-MSCsPRL-1 improved respirational metabolic states of mitochondria. In particular, mitochondria in PD-MSCsPRL-1 generated by the nonviral AMAXA system showed a significant increase in the respirational metabolic state, including ATP production and mitochondrial biogenesis (*p<0.05). Furthermore, transplantation of PD-MSCsPRL-1 using a nonviral AMAXA system promoted engraftment into injured target liver tissues of a rat BDL cirrhotic model and enhanced the metabolism of mitochondria via increased mtDNA and ATP production, thereby improving therapeutic efficacy.
Conclusions: Our findings will further our understanding of the therapeutic mechanism of enhanced MSCs and provide useful data for the development of next-generation MSC-based cell therapy and therapeutic strategies for regenerative medicine in liver disease.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
This is a list of supplementary files associated with this preprint. Click to download.
- revisedSupplementaryFigure1Kimetal.tif
Supplementary Fig. 1 Quantification of mitochondrial metabolism-specific genes in naïve and PD-MSCsPRL-1 using both gene delivery systems. Data from each group are shown as the mean ± SD. *p < 0.05 versus naïve; #p < 0.05 versus lenti. COX10; cytochrome c oxidase 10, Cyt c; cytochrome c, GAPDH; glyceraldehyde 3-phosphate dehydrogenase, HSP60; heat shock protein 60, PDH; pyruvate dehydrogenase, PHB1; prohibitin 1, SDHA; succinate dehydrogenase, SOD1; superoxide dismutase 1, VDAC; voltage-dependent anion channel
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