Mesenchymal stem cells in drug/gene delivery: implications for cell therapy

Abstract 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 using a nonviral sysyem (2 × 106 cells/animal) were intravenously administered into cirrhotic rats. 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.

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Enhanced PRL-1 expression in placenta-derived mesenchymal stem cells accelerates hepatic function via mitochondrial dynamics in a cirrhotic rat model

10.21203/rs.3.rs-22313/v2 ◽

2020 ◽

Author(s):

Jae Yeon Kim ◽

Jong Ho Choi ◽

Ji Hye Jun ◽

Sohae Park ◽

Jieun Jung ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Gene Delivery ◽

Cell Therapy ◽

Delivery Systems ◽

Nonviral Gene Delivery ◽

Early Gene ◽

Next Generation ◽

Atp Production ◽

Mitochondrial Functions

Abstract 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.

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Enhanced PRL-1 expression in placenta-derived mesenchymal stem cells accelerates hepatic function via mitochondrial dynamics in a cirrhotic rat model

10.21203/rs.3.rs-22313/v3 ◽

2020 ◽

Author(s):

Jae Yeon Kim ◽

Jong Ho Choi ◽

Ji Hye Jun ◽

Sohae Park ◽

Jieun Jung ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Gene Delivery ◽

Cell Therapy ◽

Delivery Systems ◽

Nonviral Gene Delivery ◽

Early Gene ◽

Next Generation ◽

Atp Production ◽

Mitochondrial Functions

Abstract 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.

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Enhanced PRL-1 expression in placenta-derived mesenchymal stem cells accelerates hepatic function via mitochondrial dynamics in a cirrhotic rat model

10.21203/rs.3.rs-22313/v1 ◽

2020 ◽

Author(s):

Jae Yeon Kim ◽

Jong Ho Choi ◽

Ji Hye Jun ◽

Sohae Park ◽

Jieun Jung ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Gene Delivery ◽

Regenerative Medicine ◽

Cell Therapy ◽

Rat Model ◽

Delivery Systems ◽

Metabolic State ◽

Atp Production ◽

Mitochondrial Functions

Abstract Background: Placenta-derived mesenchymal stem cells (PD-MSCs) have been highlighted as an alternative cell therapy agent that becomes a next-generation stem cell treatment because of several advantages, including therapeutic effects in regenerative medicine and potential as vehicles for targeted gene delivery systems. Phosphatase of regenerating liver-1 (PRL-1), an immediate early gene, plays a critical role during liver regeneration. However, whether enhanced PRL-1 expression in cirrhotic liver accelerates the mitochondrial metabolic state for hepatic regeneration remains unknown. 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 model with bile duct ligation (BDL). Methods: PD-MSCsPRL-1 were generated by lentiviral and non-viral AMAXA gene delivery systems and analyzed for their characteristics and mitochondrial metabolic functions. Sprague-Dawley (SD) rats induced liver cirrhosis using common BDL for 10 days. PKH67+ naïve and PD-MSCsPRL-1 using a non-viral system (2x106 cells/animal) were intravenously administered into cirrhotic rats. 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 using lentiviral and non-viral AMAXA systems were successfully generated, and they maintained characteristics similar to those of naïve cells. PD-MSCsPRL-1 improved respirational metabolic states in mitochondria compared with naïve cells. In particular, compared with mitochondria in PD-MSCsPRL-1 generated by the nonviral AMAXA system, mitochondria in PD-MSCsPRL-1 generated by the lentiviral 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 cirrhotic model with BDL 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.

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Placenta-derived mesenchymal stem cells for allogenic cardiac cell therapy

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0031-1297675 ◽

2012 ◽

Vol 60 (S 01) ◽

Cited By ~ 1

Author(s):

R Roy ◽

M Kukucka ◽

D Messroghli ◽

A Brodarac ◽

M Becher ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Therapy ◽

Cardiac Cell ◽

Cardiac Cell Therapy

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Autologous transplantation of mesenchymal stem cells into the portal vein of the miniature pig; a preliminary experiment for NOTES approach

Perspectives in Surgery ◽

10.33699/pis.2019.98.9.350-355 ◽

2019 ◽

Vol 98 (9) ◽

pp. 350-355

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Therapy ◽

Portal Vein ◽

Liver Parenchyma ◽

Miniature Pig ◽

Hepatic Diseases ◽

Study Results

Introduction: There is evidence that mesenchymal stem cells (MSCs) could trans-differentiate into the liver cells in vitro and in vivo and thus may be used as an unfailing source for stem cell therapy of liver disease. Combination of MSCs (with or without their differentiation in vitro) and minimally invasive procedures as laparoscopy or Natural Orifice Transluminal Endoscopic Surgery (NOTES) represents a chance for many patients waiting for liver transplantation in vain. Methods: Over 30 millions of autologous MSCs at passage 3 were transplanted via the portal vein in an eight months old miniature pig. The deposition of transplanted cells in liver parenchyma was evaluated histologically and the trans-differential potential of CM-DiI labeled cells was assessed by expression of pig albumin using immunofluorescence. Results: Three weeks after transplantation we detected the labeled cells (solitary, small clusters) in all 10 samples (2 samples from each lobe) but no diffuse distribution in the samples. The localization of CM-DiI+ cells was predominantly observed around the portal triads. We also detected the localization of albumin signal in CM-DiI labeled cells. Conclusion: The study results showed that the autologous MSCs (without additional hepatic differentiation in vitro) transplantation through the portal vein led to successful infiltration of intact miniature pig liver parenchyma with detectable in vivo trans-differentiation. NOTES as well as other newly developed surgical approaches in combination with cell therapy seem to be very promising for the treatment of hepatic diseases in near future.

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Innovative Cell Therapy in the Treatment of Serious Adverse Events Related to Both Chemo-Radiotherapy Protocol and Acute Myeloid Leukemia Syndrome: The Infusion of Mesenchymal Stem Cells Post-Treatment Reduces Hematopoietic Toxicity and Promotes Hematopoietic Reconstitution

Current Pharmaceutical Biotechnology ◽

10.2174/1389201014666131227120222 ◽

2014 ◽

Vol 14 (9) ◽

pp. 842-848 ◽

Cited By ~ 10

Author(s):

Loic Fouillard ◽

Sabine Francois ◽

Sandrine Bouchet ◽

Morad Bensidhoum ◽

Abdelatif Elm’selmi ◽

...

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Mesenchymal Stem Cells ◽

Adverse Events ◽

Cell Therapy ◽

Myeloid Leukemia ◽

Serious Adverse Events ◽

Hematopoietic Reconstitution ◽

Hematopoietic Toxicity ◽

Acute Myeloid

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Comparative analysis of mouse bone marrow and adipose tissue mesenchymal stem cells for critical limb ischemia cell therapy

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02110-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Pegah Nammian ◽

Seyedeh-Leili Asadi-Yousefabad ◽

Sajad Daneshi ◽

Mohammad Hasan Sheikhha ◽

Seyed Mohammad Bagher Tabei ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Adipose Tissue ◽

Cell Therapy ◽

Femoral Artery ◽

Critical Limb Ischemia ◽

Limb Ischemia

Abstract Introduction Critical limb ischemia (CLI) is the most advanced form of peripheral arterial disease (PAD) characterized by ischemic rest pain and non-healing ulcers. Currently, the standard therapy for CLI is the surgical reconstruction and endovascular therapy or limb amputation for patients with no treatment options. Neovasculogenesis induced by mesenchymal stem cells (MSCs) therapy is a promising approach to improve CLI. Owing to their angiogenic and immunomodulatory potential, MSCs are perfect candidates for the treatment of CLI. The purpose of this study was to determine and compare the in vitro and in vivo effects of allogeneic bone marrow mesenchymal stem cells (BM-MSCs) and adipose tissue mesenchymal stem cells (AT-MSCs) on CLI treatment. Methods For the first step, BM-MSCs and AT-MSCs were isolated and characterized for the characteristic MSC phenotypes. Then, femoral artery ligation and total excision of the femoral artery were performed on C57BL/6 mice to create a CLI model. The cells were evaluated for their in vitro and in vivo biological characteristics for CLI cell therapy. In order to determine these characteristics, the following tests were performed: morphology, flow cytometry, differentiation to osteocyte and adipocyte, wound healing assay, and behavioral tests including Tarlov, Ischemia, Modified ischemia, Function and the grade of limb necrosis scores, donor cell survival assay, and histological analysis. Results Our cellular and functional tests indicated that during 28 days after cell transplantation, BM-MSCs had a great effect on endothelial cell migration, muscle restructure, functional improvements, and neovascularization in ischemic tissues compared with AT-MSCs and control groups. Conclusions Allogeneic BM-MSC transplantation resulted in a more effective recovery from critical limb ischemia compared to AT-MSCs transplantation. In fact, BM-MSC transplantation could be considered as a promising therapy for diseases with insufficient angiogenesis including hindlimb ischemia.

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