Abstract
Background: Regenerative medicine strategies employing nephron progenitor cells (NPCs) are a viable approach that is worthy of substantial consideration as a promising cell source for kidney diseases. However, the generation of induced nephron progenitor-like cells (iNPCs) from human somatic cells remains a major challenge. Here, we describe a novel method for generating NPCs from human urine-derived cells (UCs) that can undergo long-term expansion in a serum-free condition. Results: Here, we generated iNPCs from human urine-derived cells by forced expression of the transcription factors OCT4, SOX2, KLF4, c-MYC, and SLUG, followed by exposure to a cocktail of defined small molecules. These iNPCs resembled human embryonic stem cell-derived NPCs in terms of their morphology, biological characteristics, differentiation potential, and global gene expression and underwent a long-term expansion in serum-free conditions. Conclusion: This study demonstrates that human iNPCs can be readily generated and expanded, which will facilitate their broad applicability in a rapid, efficient, and patient-specific manner, particularly holding the potential as a transplantable cell source for patients with kidney disease.
Highlights
Chronic kidney disease (CKD) has emerged as a major public health concern due to its prevalence in 7–12% of the population worldwide, progression to irreversible endstage renal disease (ESRD), impaired quality of life, associations with high social and financial costs, and high rates of associated morbidity and mortality [1,2]
Based on previous evidence [17,20] and our preliminary results in combination with renal-specific transcription factors (TFs), we selected five TFs that potentially participate in inducing the nephron progenitor cells (NPCs) phenotype (OSR1, SIX1, SIX2, and PAX2) or promote reprogramming as an epithelial-tomesenchymal transition (EMT) regulator (SLUG) for screening NPC-inducting TFs
We investigated whether OSKM in combination with SLUG, enabling to regulate EMT, has a synergistic effect on the generation of induced nephron progenitor-like cells (iNPCs) from urine-derived cells (UCs) and allows these cells to maintain their phenotype
Summary
Chronic kidney disease (CKD) has emerged as a major public health concern due to its prevalence in 7–12% of the population worldwide, progression to irreversible endstage renal disease (ESRD), impaired quality of life, associations with high social and financial costs, and high rates of associated morbidity and mortality (an 82% increase in CKD epidemic over the past two decades) [1,2]. Considering that the average life expectancy of dialysis patients is barely a decade, alternative strategies for preventing or delaying the progression to ESRD are urgently needed In this context, the transplantation of renal stem/progenitor cells is an attractive approach for replenishing damaged renal tissues. Results: Here, we generated iNPCs from human urine-derived cells by forced expression of the transcription factors OCT4, SOX2, KLF4, c-MYC, and SLUG, followed by exposure to a cocktail of defined small molecules These iNPCs resembled human embryonic stem cell-derived NPCs in terms of their morphology, biological characteristics, differentiation potential, and global gene expression and underwent a long-term expansion in serum-free conditions. Conclusion: This study demonstrates that human iNPCs can be readily generated and expanded, which will facilitate their broad applicability in a rapid, efficient, and patient-specific manner, holding the potential as a transplantable cell source for patients with kidney disease
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