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Functional compensation precedes recovery of tissue mass following acute liver injury.

ABSTRACT: The liver plays a central role in metabolism, protein synthesis and detoxification. It possesses unique regenerative capacity upon injury. While many factors regulating cellular proliferation during liver repair have been identified, the mechanisms by which the injured liver maintains vital functions prior to tissue recovery are unknown. Here, we identify a new phase of functional compensation following acute liver injury that occurs prior to cellular proliferation. By coupling single-cell RNA-seq with in situ transcriptional analyses in two independent murine liver injury models, we discover adaptive reprogramming to ensure expression of both injury response and core liver function genes dependent on macrophage-derived WNT/β-catenin signaling. Interestingly, transcriptional compensation is most prominent in non-proliferating cells, clearly delineating two temporally distinct phases of liver recovery. Overall, our work describes a mechanism by which the liver maintains essential physiological functions prior to cellular reconstitution and characterizes macrophage-derived WNT signals required for this compensation.

SUBMITTER: Walesky CM

PROVIDER: S-EPMC7677389 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Functional compensation precedes recovery of tissue mass following acute liver injury.

Walesky Chad M CM Kolb Kellie E KE Winston Carolyn L CL Henderson Jake J Kruft Benjamin B Fleming Ira I Ko Sungjin S Monga Satdarshan P SP Mueller Florian F Apte Udayan U Shalek Alex K AK Goessling Wolfram W

Nature communications 20201119 1

The liver plays a central role in metabolism, protein synthesis and detoxification. It possesses unique regenerative capacity upon injury. While many factors regulating cellular proliferation during liver repair have been identified, the mechanisms by which the injured liver maintains vital functions prior to tissue recovery are unknown. Here, we identify a new phase of functional compensation following acute liver injury that occurs prior to cellular proliferation. By coupling single-cell RNA-s ...[more]

PMID: 33214549

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Project description:BackgroundRecent data have shown that severe acute respiratory syndrome coronavirus 2 can infect renal proximal tubular cells via Angiotensin Converting Enzyme 2 (ACE2) . Our objective was to determine whether Fanconi syndrome is a frequent clinical feature in coronavirus disease 2019 (COVID-19) patients.MethodsA retrospective cohort of 42 laboratory-confirmed COVID-19 patients without history of kidney disease hospitalized in University Hospital of Nancy was investigated. Patients were admitted to the intensive care unit (ICU) (n = 28) or the Medical department (n = 14) and were screened at least once for four markers of proximal tubulopathy.ResultsThe mean (standard deviation) follow-up was 19.7 (±12.2) days. Of the patients, 75% (30/40) showed at least two proximal tubule abnormalities (incomplete Fanconi syndrome). The main disorders were proteinuria (88%, n = 35), renal phosphate leak defined by renal phosphate threshold/glomerular filtration rate (TmPi/GFR) <0.77 (55%, n = 22), hyperuricosuria (43%, n = 17) and normoglycaemic glycosuria (30%, n = 12). At the time of the first renal evaluation, ICU patients presented more frequent (96 versus 62%, P = 0.0095) and more severe (844 ± 343 versus 350 ± 221 mg/g, P = 0.0001) proteinuria, and a trend for an increased number of proximal tubule abnormalities (P = 0.038). During follow-up, they presented a lower nadir of serum phosphate [median (interquartile range) 0.68 (0.43-0.76) versus 0.77 (0.66-1.07) mmol/L, P = 0.044] and Acute kidney Injury (AKI) during the hospitalization (P = 0.045). Fanconi syndrome preceded severe AKI KDIGO Stages 2 and 3 in 88% (7/8) of patients. Proximal tubular abnormalities (such as proteinuria, TmPi/GFR and glycosuria in five, two and two patients, respectively) were not detected anymore in recovering patients before hospital discharge.ConclusionIncomplete Fanconi syndrome is highly frequent in COVID-19 patients and precedes AKI or disappears during the recovery phase.

Project description:The quality of arm movements typically improves in the sub-acute phase of stroke affecting the upper extremity. Here, we used whole arm kinematic analysis during reaching movements to distinguish whether these improvements are due to true recovery or to compensation. Fifty-three participants with post-acute stroke performed ∼80 reaching movement tests during 4 weeks of training with the ArmeoSpring exoskeleton. All participants showed improvements in end-effector performance, as measured by movement smoothness. Four ArmeoSpring angles, shoulder horizontal (SH) rotation, shoulder elevation (SE), elbow rotation, and forearm rotation, were recorded and analyzed. We first characterized healthy joint coordination patterns by performing a sparse principal component analysis on these four joint velocities recorded during reaching tests performed by young control participants. We found that two dominant joint correlations [SH with elbow rotation and SE with forearm rotation] explained over 95% of variance of joint velocity data. We identified two clusters of stroke participants by comparing the evolution of these two correlations in all tests. In the "Recoverer" cluster (N = 19), both joint correlations converged toward the respective correlations for control participants. Thus, Recoverers relearned how to generate smooth end-effector movements while developing joint movement patterns similar to those of control participants. In the "Compensator" cluster (N = 34), at least one of the two joint correlations diverged from the corresponding correlation of control participants. Compensators relearned how to generate smooth end-effector movements by discovering various new compensatory movement patterns dissimilar to those of control participants. New compensatory patterns included atypical decoupling of the SE and forearm joints, and atypical coupling of the SH rotation and elbow joints. There was no difference in clinical impairment level between the two groups either at the onset or at the end of training as assessed with the Upper Extremity Fugl-Meyer scale. However, at the start of training, the Recoverers showed significantly faster improvements in end-effector movement smoothness than the Compensators. Our analysis can be used to inform neurorehabilitation clinicians on how to provide movement feedback during practice and suggest avenues for refining exoskeleton robot therapy to reduce compensatory patterns.

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Functional compensation precedes recovery of tissue mass following acute liver injury.

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Functional compensation precedes recovery of tissue mass following acute liver injury.

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