Protect TUDCA stimulated CKD-derived hMSCs against the CKD-Ischemic disease via upregulation of PrPC

Although autologous human mesenchymal stem cells (hMSCs) are a promising source for regenerative stem cell therapy, the barriers associated with pathophysiological conditions in this disease limit therapeutic applicability to patients. We proved treatment of CKD-hMSCs with TUDCA enhanced the mitochondrial function of these cells and increased complex I & IV enzymatic activity, increasing PINK1 expression and decreasing mitochondrial O2•− and mitochondrial fusion in a PrPC-dependent pathway. Moreover, TH-1 cells enhanced viability when co-cultured in vitro with TUDCA-treated CKD-hMSC. In vivo, tail vein injection of TUDCA-treated CKD-hMSCs into the mouse model of CKD associated with hindlimb ischemia enhanced kidney recovery, the blood perfusion ratio, vessel formation, and prevented limb loss, and foot necrosis along with restored expression of PrPC in the blood serum of the mice. These data suggest that TUDCA-treated CKD-hMSCs are a promising new autologous stem cell therapeutic intervention that dually treats cardiovascular problems and CKD in patients.

[1]  D. Komander,et al.  Mechanism of parkin activation by PINK1 , 2018, Nature.

[2]  J. Forbes,et al.  Mitochondrial dysfunction in diabetic kidney disease , 2018, Nature Reviews Nephrology.

[3]  Zhihong Liu,et al.  Klotho restoration via acetylation of Peroxisome Proliferation-Activated Receptor γ reduces the progression of chronic kidney disease. , 2017, Kidney international.

[4]  G. Qin,et al.  FoxO1 Promotes Mitophagy in the Podocytes of Diabetic Male Mice via the PINK1/Parkin Pathway , 2017, Endocrinology.

[5]  C. Rodrigues,et al.  Tauroursodeoxycholic Acid Enhances Mitochondrial Biogenesis, Neural Stem Cell Pool, and Early Neurogenesis in Adult Rats , 2017, Molecular Neurobiology.

[6]  J. Launay,et al.  The Cellular Prion Protein Controls Notch Signaling in Neural Stem/Progenitor Cells , 2017, Stem cells.

[7]  E. Fischer,et al.  Cellular prion protein is present in mitochondria of healthy mice , 2017, Scientific Reports.

[8]  S. Yun,et al.  Tauroursodeoxycholic acid reduces ER stress by regulating of Akt-dependent cellular prion protein , 2016, Scientific Reports.

[9]  J. M. Ryu,et al.  Fucoidan improves bioactivity and vasculogenic potential of mesenchymal stem cells in murine hind limb ischemia associated with chronic kidney disease. , 2016, Journal of molecular and cellular cardiology.

[10]  A. Urbani,et al.  Slow intestinal transit contributes to elevate urinary p‐cresol level in Italian autistic children , 2016, Autism research : official journal of the International Society for Autism Research.

[11]  R. Stratta,et al.  Kidney transplantation, bioengineering and regeneration: an originally immunology-based discipline destined to transition towards ad hoc organ manufacturing and repair , 2016, Expert review of clinical immunology.

[12]  C. Reutelingsperger,et al.  Vascular calcification in chronic kidney disease: an update. , 2016, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[13]  C. Klein,et al.  The cellular prion protein PrPc is a partner of the Wnt pathway in intestinal epithelial cells , 2015, Molecular biology of the cell.

[14]  R. Linden,et al.  Activation and function of murine primary microglia in the absence of the prion protein , 2015, Journal of Neuroimmunology.

[15]  A. Szabó,et al.  Fibrosis Related Inflammatory Mediators: Role of the IL-10 Cytokine Family , 2015, Mediators of inflammation.

[16]  J. Burdick,et al.  Local immunotherapy via delivery of interleukin-10 and transforming growth factor β antagonist for treatment of chronic kidney disease. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[17]  Janet S. Lee,et al.  PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. , 2015, The Journal of clinical investigation.

[18]  H. Tse,et al.  Paracrine Mechanisms of Mesenchymal Stem Cell-Based Therapy: Current Status and Perspectives , 2014, Cell transplantation.

[19]  B. Urquhart,et al.  Pharmacokinetic considerations in chronic kidney disease and patients requiring dialysis , 2014, Expert opinion on drug metabolism & toxicology.

[20]  P. Boor,et al.  Mesenchymal Stem Cells from Rats with Chronic Kidney Disease Exhibit Premature Senescence and Loss of Regenerative Potential , 2014, PloS one.

[21]  Lin Sun,et al.  Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology , 2012, Kidney international.

[22]  D. Cusi,et al.  Vascular Calcification in Chronic Kidney Disease: An Update , 2013, EMJ Nephrology.

[23]  R. Youle,et al.  Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. , 2012, Developmental cell.

[24]  F. Levander,et al.  Relative quantification of membrane proteins in wild-type and prion protein (PrP)-knockout cerebellar granule neurons. , 2012, Journal of proteome research.

[25]  Kindiya D. Geghman,et al.  Pink1 regulates the oxidative phosphorylation machinery via mitochondrial fission , 2011, Proceedings of the National Academy of Sciences.

[26]  P. Reddien,et al.  The cellular basis for animal regeneration. , 2011, Developmental cell.

[27]  R. Youle,et al.  Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. , 2011, Antioxidants & redox signaling.

[28]  K. Verbeke,et al.  p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[29]  Thomas Korff,et al.  Evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia , 2009, Nature Protocols.

[30]  D. Westaway,et al.  Prion protein expression and release by mast cells after activation. , 2009, The Journal of infectious diseases.

[31]  J. Coresh,et al.  CKD surveillance using laboratory data from the population-based National Health and Nutrition Examination Survey (NHANES). , 2009, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[32]  A. Uccelli,et al.  Mesenchymal stem cells in health and disease , 2008, Nature Reviews Immunology.

[33]  M. Little,et al.  Regrow or Repair: Potential Regenerative Therapies for the Kidney Regenerative Approaches to Renal Disease Setting the Stage: Normal Kidney Development and Regeneration in Vertebrates , 2022 .

[34]  Andrew D. Steele,et al.  Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Bianchin,et al.  Normal brain mitochondrial respiration in adult mice lacking cellular prion protein , 2005, Neuroscience Letters.

[36]  Bertram L Kasiske,et al.  Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. , 2003, Hypertension.

[37]  R. D'Hooge,et al.  Involvement of voltage- and ligand-gated Ca2+ channels in the neuroexcitatory and synergistic effects of putative uremic neurotoxins. , 2003, Kidney international.

[38]  C. Rodrigues,et al.  Membrane structural changes support the involvement of mitochondria in the bile salt-induced apoptosis of rat hepatocytes. , 2002, Clinical science.

[39]  D. Turnbull,et al.  Ablation of cellular prion protein expression affects mitochondrial numbers and morphology. , 2002, Biochemical and biophysical research communications.

[40]  David R. Brown,et al.  Lack of prion protein expression results in a neuronal phenotype sensitive to stress , 2002, Journal of neuroscience research.

[41]  F. Cohen,et al.  Prion Protein Biology , 1998, Cell.

[42]  J. Lakey,et al.  Copper binding to the N-terminal tandem repeat region of mammalian and avian prion protein: structural studies using synthetic peptides. , 1995, Biochemical and biophysical research communications.

[43]  S. Prusiner.  Novel proteinaceous infectious particles cause scrapie. , 1982, Science.