The ability to replace defective cells in an airway with cells that can engraft, integrate, and restore a functional epithelium could potentially cure a number of lung diseases. Progress toward the development of strategies to regenerate the adult lung by either in vivo or ex vivo targeting of endogenous stem cells or pluripotent stem cell derivatives is limited by our fundamental lack of understanding of the mechanisms controlling human lung development, the precise identity and function of human lung stem and progenitor cell types, and the genetic and epigenetic control of human lung fate. In this review, we intend to discuss the known stem/progenitor cell populations, their relative differences between rodents and humans, their roles in chronic lung disease, and their therapeutic prospects. Additionally, we highlight the recent breakthroughs that have increased our understanding of these cell types. These advancements include novel lineage-traced animal models and single-cell RNA sequencing of human airway cells, which have provided critical information on the stem cell subtypes, transition states, identifying cell markers, and intricate pathways that commit a stem cell to differentiate or to maintain plasticity. As our capacity to model the human lung evolves, so will our understanding of lung regeneration and our ability to target endogenous stem cells as a therapeutic approach for lung disease.

https://journals.physiology.org/doi/pdf/10.1152/ajpcell.00036.2020

Stem cells and lung regeneration

Background
Kidney transplantation is the preferred form of kidney replacement therapy for patients with end-stage kidney disease (ESKD) and is often complicated by worsening or new-onset diabetes. Management of hyperglycaemia is important to reduce post-transplant and diabetes-related complications. The safety and efficacy of glucose-lowering agents after kidney transplantation is largely unknown.

Objectives
To evaluate the efficacy and safety of pharmacological interventions for lowering glucose levels in patients who have undergone kidney transplantation and have diabetes.

Search methods
We searched the Cochrane Kidney and Transplant Specialised Register to 15 April 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria
All randomised controlled trials (RCTs), quasi-RCTs and cross-over studies examining head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in patients who have received a kidney transplant and have diabetes were eligible for inclusion.

Data collection and analysis
Two authors independently assessed study eligibility and quality and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD) or standardised mean difference (SMD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI).

Main results
We included seven studies that involved a total of 399 kidney transplant recipients. All included studies had observed heterogeneity in the patient population, interventions and measured outcomes or missing data (which was unavailable despite correspondence with authors). Many studies had incompletely reported methodology preventing meta-analysis and leading to low confidence in treatment estimates.

Three studies with 241 kidney transplant recipients examined the use of more intensive compared to less intensive insulin therapy in kidney transplant recipients with pre-existing type 1 or 2 diabetes. Evidence for the effects of more intensive compared to less intensive insulin therapy on transplant graft survival, HbA1c, fasting blood glucose, all cause mortality and adverse effects including hypoglycaemia was of very low quality. More intensive versus less intensive insulin therapy resulted in no difference in transplant or graft survival over three to five years in one study while another study showed that more intensive versus less intensive insulin therapy resulted in more rejection events over the three year follow-up (11 events in total; 9 in the more intensive group, P = 0.01). One study showed that more intensive insulin therapy resulted in a lower mean HbA1c (10 ± 0.8% versus 13 ± 0.9%) and lower fasting blood glucose (7.22 ± 0.5 mmol/L versus 13.44 ± 1.22 mmol/L) at 13 months compared with standard insulin therapy. Another study showed no difference between more intensive compared to less intensive insulin therapy on all-cause mortality over a five year follow-up period. All studies showed either an increased frequency of hypoglycaemia or severe hypoglycaemia episodes.

Three studies with a total of 115 transplant recipients examined the use of DPP4 inhibitors for new-onset diabetes after transplantation. Evidence for the treatment effect of DPP4 inhibitors on transplant or graft survival, HbA1c and fasting blood glucose levels, all cause mortality, and adverse events including hypoglycaemia was of low quality. One study comparing vildagliptin to placebo and another comparing sitagliptin to placebo showed no difference in transplant or graft survival over two to four months of follow-up. One study comparing vildagliptin to placebo showed no significant change in estimated glomerular filtration rate from baseline (1.9 ± 10.3 mL/min/1.73 m2, P = 0.48 and 2.1 ± 6.1 mL/min/1.73 m2, P = 0.22) and no deaths, in either treatment group over three months of follow-up. One study comparing vildagliptin to placebo showed a lower HbA1c level (mean ± SD) (6.3 ± 0.5% versus versus 6.7 ± 0.6%, P = 0.03) and trend towards a greater lowering of fasting blood glucose (-0.91 ± -0.92 mmol/L versus vs -0.19 ± 1.16 mmol/L, P = 0.08) with vildagliptin. One study comparing sitagliptin to insulin glargine showed an equivalent lowering of HbA1c (-0.6 ± 0.5% versus -0.6 ± 0.6%, P = NS) and fasting blood glucose (4.92 ± 1.42 versus 4.76 ± 1.09 mmol/L, P = NS) with sitagliptin. For the outcome of hypoglycaemia, one study comparing vildagliptin to placebo reported no episodes of hypoglycaemia, one study comparing sitagliptin to insulin glargine reported fewer episodes of hypoglycaemia with sitagliptin (3/28 patients; 10.7% versus 5/28; 17.9%) and one cross-over study of sitagliptin and placebo reported two episodes of asymptomatic moderate hypoglycaemia (2 to 3.9 mmol/L) when sitagliptin was administered with glipizide. All three studies reported no drug interactions between DPP4 inhibitors and the immunosuppressive agents taken.

Evidence for the treatment effect of pioglitazone for treating pre-existing diabetes was of low quality. One study with 62 transplant recipients compared the use of pioglitazone with insulin to insulin alone for treating pre-existing diabetes. Pioglitazone resulted in a lower HbA1c level (mean ± SD) (-1.21 ± 1.2 versus 0.39 ± 1%, P < 0.001) but had no effects on fasting blood glucose (6.58 ± 2.71 versus 7.28 ± 2.78 mmol/L, P = 0.14 ), and change in creatinine (3.54 ± 15.03 versus 10.61 ± 18.56 mmol/L, P = 0.53) and minimal adverse effects (no episodes of hypoglycaemia, three dropped out due to mild to moderate lower extremity oedema, cyclosporin levels were not affected).

Authors' conclusions
Evidence concerning the efficacy and safety of glucose-lowering agents for treating pre-existing and new-onset diabetes in kidney transplant recipients is limited. Existing studies examine more intensive versus less intensive insulin therapy, and the use of DPP4 inhibitors and pioglitazone. The safety and efficacy of more intensive compared to less intensive insulin therapy is very uncertain and the safety and efficacy of DPP4 inhibitors and pioglitazone is uncertain, due to data being limited and of poor quality. Additional RCTs are required to clarify the safety and efficacy of current glucose-lowering agents for kidney transplant recipients with diabetes.

/pdf/glucose-lowering-agents-for-treating-pre-existing-and-new-2y4a5qciub.pdf

Glucose-lowering agents for treating pre-existing and new-onset diabetes in kidney transplant recipients.

The domestic ferret (Mustela putorius furo) has proven to be a useful species for modeling human genetic and infectious diseases of the lung and brain. However, biomedical research in ferrets has been hindered by the lack of rapid and cost-effective methods for genome engineering. Here, we utilized CRISPR/Cas9-mediated, homology-independent insertion at the ROSA26 “safe harbor” locus in ferret zygotes and created transgenic animals expressing a dual-fluorescent Cre-reporter system flanked by PhiC31 and Bxb1 integrase attP sites. Out of 151 zygotes injected with circular transgene-containing plasmid and Cas9 protein loaded with the ROSA26 intron-1 sgRNA, there were 23 births of which 5 had targeted integration events (22% efficiency). The encoded tdTomato transgene was highly expressed in all tissues evaluated. Targeted integration was verified by PCR analyses, Southern blot, and germ-line transmission. Function of the ROSA26-CAG-LoxPtdTomatoStopLoxPEGFP (ROSA-TG) Cre-reporter was confirmed in primary cells following Cre expression. The Phi31 and Bxb1 integrase attP sites flanking the transgene will also enable rapid directional insertion of any transgene without a size limitation at the ROSA26 locus. These methods and the model generated will greatly enhance biomedical research involving lineage tracing, the evaluation of stem cell therapy, and transgenesis in ferret models of human disease.

/pdf/highly-efficient-transgenesis-in-ferrets-using-crispr-cas9-2svta4vpq9.pdf

Highly Efficient Transgenesis in Ferrets Using CRISPR/Cas9-Mediated Homology-Independent Insertion at the ROSA26 Locus.

Uterine sensitization-associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor-related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti-USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti-USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

/pdf/anti-usag-1-therapy-for-tooth-regeneration-through-enhanced-5biivettwi.pdf

Anti-USAG-1 therapy for tooth regeneration through enhanced BMP signaling.

Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD)—the major limitation to long-term survival following lung transplantati...

Airway Epithelial Telomere Dysfunction Drives Remodeling Similar to Chronic Lung Allograft Dysfunction.

257 Rapid health decline in young cystic fibrosis transmembrane conductance regulatorG551D ferrets after discontinuation of cystic fibrosis transmembrane conductance regulator modulator

602 Optimization of cystic fibrosis transmembrane conductance regulatorG551D ferret model for early synchronized lung microbial colonization

425 Development of an AICDA-CreERT2 ferret model to study adaptive humoral immunity

258 Impact of temporal changes in cystic fibrosis transmembrane conductance regulator activity on fertility, conception, pregnancy, and lactation in ferrets with cystic fibrosis

Background: Osmoregulation, which maintains the osmolarity of fluid surrounding cells, is a key feature of ionocytes across species and has been studied extensively in fish adaptation to environmental changes in salinity.In the mammalian kidney, osmoregulation is coordinated by principal cells and intercalated cells of the collecting ducts, which control water movement; acid-base regulation; and Na + , Cl -, K + , and Ca 2+ homeostasis.Given the overlap in expressed channels between pulmonary ionocytes and kidney principal cells and intercalated cells, we hypothesized that pulmonary ionocytes may also participate in osmoregulation by airway epithelia.Methods: To mimic fish gill ionocytes in freshwater and seawater environments, we created hypertonic and hypotonic air-liquid interface (ALI) culture media.FOXI1-Cre ERT2 lineage-traced proximal airway stem cells were differentiated under hypertonic or hypotonic conditions in ALI culture.At full differentiation (21 days), we quantified ionocyte numbers and ionocyte subtype gene expression patterns.Results: We exposed actively differentiating ferret basal cells to slightly hypertonic media (+77 mOsm/L NaCl) and observed a marked increase (7.32-fold; p < 0.0015) in the number of lineage-traced pulmonary ionocytes at full differentiation (21 days).Under hyperosmotic stress, greater numbers of ionocytes was correlated with high mRNA expression of key ionocyte markers FOXI1 and ASCL3.We have previously shown that three ionocyte subtypes exist (Type-A, Type-B, Type-C) in ferret airway ALI culture.We found that hyperosmotic stress increased expression of Type-A (BSND) and Type-C (CXCL17) ionocyte marker genes but decreased expression of the Type-B ionocyte marker ID3.The observed downregulation in CFTR expression under hyperosmotic stress is consistent with the expansion of Type-C ionocytes, which express significantly ( p = 2 × 10 -11 ) less CFTR than other ionocyte subtypes.Hyperosmotic stress imposed on fully differentiated ALI cultures did not alter the frequency of lineage-traced pulmonary ionocytes, suggesting that a hyperosmotic environment affects progenitor cell specification of Type-A and Type-C ionocytes.Exposure of differentiating ferret basal cells to hypotonic media (-77 mOsm/L) also led to expansion of ATP6V1G3 + ionocytes when fully differentiated at the ALI.Ongoing gene expression profiling is defining the dominant ionocyte subtype under hypotonic conditions.Conclusions: These findings indicate that osmolarity affects basal cell specification of pulmonary ionocytes and suggests that there are specialized ionocyte functions that adapt to environmental changes in airway osmolarity.Hyperosmotic fluid at the basolateral surface of the airway would be expected to be extracted water from cells and the airway surface liquid (ASL), leading to cell shrinkage and ASL dehydration.Our data suggest that apical membrane Cl -permeability is constrained by CFTR-expressing ionocytes and that the observed hyperosmotic downregulation of CFTR may be a compensatory mechanism to limit ASL dehydration.This finding may be analogous to the inactivation of ionocyte CFTR expression in fish gills during seawater to freshwater transition. 

163 Ferret pulmonary ionocytes abundance is regulated by extracellular osmolarity in air-liquid interface culture

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