Are Current Strategies for Building a Human Kidney Misguided? Speculative Alternatives

Fine, Leon G.

doi:10.1681/asn.2018080822

Cited by 2 publications

(1 citation statement)

References 13 publications

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“…As examples, it was reported that more mature glomerular differentiation, including formation of glomerular capillary loops, can be achieved by implanting hPSC-derived kidney tissues either subcutaneously [8, 11] or under the kidney capsule [12, 13] in immunocompromised mice. Unfortunately, there are drawbacks [3, 14] to current in vitro and in vivo technologies, including the limited size and vascularity attained by PSC-derived kidney tissues.…”

Section: Introductionmentioning

confidence: 99%

Aberrant Differentiation of Human Pluripotent Stem Cell-Derived Kidney Precursor Cells inside Mouse Vascularized Bioreactors

Ranjzad

Jinks

Salahi

et al. 2020

Nephron

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Background: Numerous studies have documented the in vitro differentiation of human pluripotent stem cells (hPSCs) into kidney cells. Fewer studies have followed the fates of such kidney precursor cells (KPCs) inside animals, a more lifelike setting. Here, we tested the hypothesis that implanting hPSC-derived KPCs into an in vivo milieu surgically engineered to be highly vascular would enhance their maturation into kidney tissues. Methods: 3D printed chambers containing KPCs were implanted into the thighs of adult immunodeficient mice. In some chambers, an arterial and venous flowthrough (AVFT) was surgically fashioned. After 3 weeks and 3 months, implants were studied by histology, using qualitative and quantitative methods. Results: After 3 weeks, chambers containing AVFTs were richer in small vessels than contralateral chambers without AVFTs. Glomeruli with capillary loops and diverse types of tubules were detected in all chambers. At 3 months, chambers contained only rudimentary tubules and glomeruli that appeared avascular. In chambers with AVFTs, prominent areas of muscle-like cells were also detected near tubules and the abnormal tissues immunostained for transforming growth factor β1. These features have similarities to renal dysplasia, a typical histological signature of human congenital kidney malformations. Conclusions: This study urges a note of caution regarding the in vivo fates of hPSC-derived kidney precursors, with pathological differentiation appearing to follow a period of increased vascularity.

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Section: Introductionmentioning

confidence: 99%

Aberrant Differentiation of Human Pluripotent Stem Cell-Derived Kidney Precursor Cells inside Mouse Vascularized Bioreactors

Ranjzad

Jinks

Salahi

et al. 2020

Nephron

View full text Add to dashboard Cite

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Bioenergetics: the evolutionary basis of progressive kidney disease

Chevalier

2023

Physiological Reviews

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Chronic kidney disease (CKD) affects over 10% of the world population with increasing prevalence in middle age. The risk for CKD is dependent on the number of functioning nephrons through the life cycle and 50% of nephrons are lost through normal aging, revealing their vulnerability to internal and external stressors. Factors responsible for CKD remain poorly understood with limited availability of biomarkers or effective therapy to slow progression. This review draws on the disciplines of evolutionary medicine and bioenergetics to account for the heterogeneous nephron injury that characterizes progressive CKD following acute kidney injury with incomplete recovery. The evolution of symbiosis in eukaryotes led to the efficiencies of oxidative phosphorylation and the rise of metazoa. Adaptations to ancestral environments are the products of natural selection that have shaped the mammalian nephron with its vulnerabilities to ischemic, hypoxic, and toxic injury. Reproductive fitness rather than longevity has served as the driver of evolution, constrained by available energy and its allocation to homeostatic responses through the life cycle. Metabolic plasticity has evolved in parallel with robustness necessary to preserve complex developmental programs, and adaptations that optimize survival through reproductive years can become maladaptive with aging, reflecting antagonistic pleiotropy. Consequently, environmental stresses promote tradeoffs and mismatches that result in cell fate decisions that ultimately lead to nephron loss. Elucidation of the bioenergetic adaptations by the nephron to ancestral and contemporary environments may lead to the development of new biomarkers of kidney disease and new therapies to reduce the global burden of progressive CKD.

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Are Current Strategies for Building a Human Kidney Misguided? Speculative Alternatives

Cited by 2 publications

References 13 publications

Aberrant Differentiation of Human Pluripotent Stem Cell-Derived Kidney Precursor Cells inside Mouse Vascularized Bioreactors

Aberrant Differentiation of Human Pluripotent Stem Cell-Derived Kidney Precursor Cells inside Mouse Vascularized Bioreactors

Bioenergetics: the evolutionary basis of progressive kidney disease

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