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Summary End-stage organ failure is a key challenge for the medical community because of the ageing population and the severe shortage of suitable donor organs available. Equally, injuries to or congenital absence of complex tissues such as the trachea, oesophagus, or skeletal muscle have few therapeutic options. A new approach to treatment involves the use of three-dimensional biological scaffolds made of allogeneic or xenogeneic extracellular matrix derived from non-autologous sources. These scaffolds can act as an inductive template for functional tissue and organ reconstruction after recellularisation with autologous stem cells or differentiated cells. Such an approach has been used successfully for the repair and reconstruction of several complex tissues such as trachea, oesophagus, and skeletal muscle in animal models and human beings, and, guided by appropriate scientific and ethical oversight, could serve as a platform for the engineering of whole organs and other tissues.

Advances in tissue engineering continue at a rapid pace and have provided novel methodologies and insights into normal cell and tissue homeostasis, disease pathogenesis, and new potential therapeutic strategies. The evolution of new techniques has particularly invigorated the field and span a range from novel organ and organoid technologies to increasingly sophisticated imaging modalities. This is particularly relevant for the field of lung biology and diseases as many lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic fibrosis (IPF), among others, remain incurable with significant morbidity and mortality. Advances in lung regenerative medicine and engineering also offer new potential avenues for critical illnesses such as the acute respiratory distress syndrome (ARDS) which also continue to have significant morbidity and mortality. In this review, an overview of lung regenerative medicine with focus on current status of both structural and functional repair will be presented. This will serve as a platform for surveying innovative models and techniques for study, highlighting the need and timeliness for these approaches.

Insecticide-treated nets (ITNs) are one of the most widespread and impactful malaria interventions in Africa, yet a spatially-resolved time series of ITN coverage has never been published. Using data from multiple sources, we generate high-resolution maps of ITN access, use, and nets-per-capita annually from 2000 to 2020 across the 40 highest-burden African countries. Our findings support several existing hypotheses: that use is high among those with access, that nets are discarded more quickly than official policy presumes, and that effectively distributing nets grows more difficult as coverage increases. The primary driving factors behind these findings are most likely strong cultural and social messaging around the importance of net use, low physical net durability, and a mixture of inherent commodity distribution challenges and less-than-optimal net allocation policies, respectively. These results can inform both policy decisions and downstream malaria analyses. Insecticide treated nets (ITNs) are an important part of malaria control in Africa and WHO targets aim for 80% coverage. This study estimates the spatio-temporal access and use of ITNs in Africa from 2000-2020, and shows that both metrics have improved over time but access remains below WHO targets.

Climatic conditions are a key determinant of malaria transmission intensity, through their impacts on both the parasite and its mosquito vectors. Mathematical models relating climatic conditions to malaria transmission can be used to develop spatial maps of climatic suitability for malaria. These maps underpin efforts to quantify the distribution and burden of malaria in humans, enabling improved monitoring and control. Previous work has developed mathematical models and global maps for the suitability of temperature for malaria transmission. In this paper, existing temperature-based models are extended to include two other important bioclimatic factors: humidity and rainfall. This model is combined with fine spatial resolution climatic data to produce a more biologically-realistic global map of climatic suitability for Plasmodium falciparum malaria. The climatic suitability index developed corresponds more closely than previous temperature suitability indices with the global distribution of P. falciparum malaria. There is weak agreement between the Malaria Atlas Project estimates of P. falciparum prevalence in Africa and the estimates of suitability solely based on temperature (Spearman Correlation coefficient of ρ = 0.24 ). The addition of humidity and then rainfall improves the comparison ( ρ = 0.62 when humidity added; ρ = 0.70 when both humidity and rainfall added). By incorporating the impacts of humidity and rainfall, this model identifies arid regions that are not climatically suitable for transmission of P. falciparum malaria. Incorporation of this improved index of climatic suitability into geospatial models can improve global estimates of malaria prevalence and transmission intensity.

Alveolar type 2 epithelial cells (AT2s) derived from human induced pluripotent stem cells (iAT2s) have rapidly contributed to our understanding of AT2 function and disease. However, while iAT2s are primarily cultured in three-dimensional (3D) Matrigel, a matrix derived from cancerous mouse tissue, it is unclear how a physiologically relevant matrix will impact iAT2s phenotype. As extracellular matrix (ECM) is recognized as a vital component in directing cellular function and differentiation, we sought to derive hydrogels from decellularized human lung alveolar-enriched ECM (aECM) to provide an ex vivo model to characterize the role of physiologically relevant ECM on iAT2 phenotype. We demonstrate aECM hydrogels retain critical in situ ECM components, including structural and basement membrane proteins. While aECM hydrogels facilitate iAT2 proliferation and alveolosphere formation, a subset of iAT2s rapidly change morphology to thin and elongated ring-like cells. This morphological change correlates with upregulation of recently described iAT2-derived transitional cell state genetic markers. As such, we demonstrate a potentially underappreciated role of physiologically relevant aECM in iAT2 differentiation.

Background We previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic MSCs (remestemcel-L) in COPD. While safety profile was good, no functional efficacy was observed. However, in view of growing recognition of effects of inflammatory environments on MSC actions we conducted a post-hoc analysis with stratification by baseline levels of a circulating inflammatory marker, C-reactive protein (CRP) to determine the effects of MSC administration in COPD patients with varying circulating CRP levels. Methods Time course of lung function, exercise performance, patient reported responses, and exacerbation frequency following four monthly infusions of remestemcel-L vs. placebo were re-assessed in subgroups based on baseline circulating CRP levels. Results In COPD patients with baseline CRP ≥ 4 mg/L, compared to COPD patients receiving placebo (N = 17), those treated with remestemcel-L (N = 12), demonstrated significant improvements from baseline in forced expiratory volume in one second, forced vital capacity, and six minute walk distance at 120 days with treatment differences evident as early as 10 days after the first infusion. Significant although smaller benefits were also detected in those with CRP levels ≥ 2 or ≥ 3 mg/L. These improvements persisted variably over the 2-year observational period. No significant benefits were observed in patient reported responses or number of COPD exacerbations between treatment groups. Conclusion In an inflammatory environment, defined by elevated circulating CRP, remestemcel-L administration yielded at least transient meaningful pulmonary and functional improvements. These findings warrant further investigation of potential MSC-based therapies in COPD and other inflammatory pulmonary diseases. Trial registration: Clinicaltrials.gov NCT00683722.

Rapid progress is occurring in understanding the mechanisms underlying mesenchymal stromal cell (MSC)-based cell therapies (MSCT). However, the results of clinical trials, while demonstrating safety, have been varied in regard to efficacy. Recent data from different groups have shown profound and significant influences of the host inflammatory environment on MSCs delivered systemically or through organ-specific routes, for example intratracheal, with subsequent actions on potential MSC efficacies. Intriguingly in some models, it appears that dead or dying cells or subcellular particles derived from them, may contribute to therapeutic efficacy, at least in some circumstances. Thus, the broad cellular changes that accompany MSC death, autophagy, pre-apoptotic function, or indeed the host response to these processes may be essential to therapeutic efficacy. In this review, we summarize the existing literature concerning the necrobiology of MSCs and the available evidence that MSCs undergo autophagy, apoptosis, transfer mitochondria, or release subcellular particles with effector function in pathologic or inflammatory environments. Advances in understanding the role of immune effector cells in cell therapy, especially macrophages, suggest that the reprogramming of immunity associated with MSCT has a weighty influence on therapeutic efficacy. If correct, these data suggest novel approaches to enhancing the beneficial actions of MSCs that will vary with the inflammatory nature of different disease targets and may influence the choice between autologous or allogeneic or even xenogeneic cells as therapeutics.

Mesenchymal stromal cells (MSCs) were identified more than 50 years ago, and research advances have promoted the translation of pre-clinical studies into clinical settings in several diseases. However, we are only starting to uncover the local factors that regulate cell phenotype, cell function, and cell viability across tissues following administration in different diseases. Advances in pre-clinical and translational studies suggest that the host environment, especially inflammatory active environments, plays a significant role in directing the infused MSCs towards different phenotypes with different functions. This can significantly effect their therapeutic efficacy. One way to study this interaction between the host environment and the infused cells is to expose MSCs ex vivo to patient samples such as serum or bronchoalveolar lavage fluid. Using this approach, it has been demonstrated that MSCs are very sensitive to different host factors such as pathogens, inflammatory cytokines, and extra cellular matrix properties. By understanding how different local host factors effect MSC function it will open possibilities to select specific patient sub-groups that are more likely to respond to this type of treatment and will also open possibilities to prime the local host environment to increase viability and to enrich for a specific MSC phenotype. Here, we aim to review the current understanding of the interaction of MSCs with the host microenvironment. To narrow the scope of this mini review, the focus will be on the pulmonary microenvironment, with a specific focus on the diseases acute respiratory distress syndrome (ARDS) and cystic fibrosis (CF).

Zika virus was discovered in Uganda in 1947 and is transmitted by Aedes mosquitoes, which also act as vectors for dengue and chikungunya viruses throughout much of the tropical world. In 2007, an outbreak in the Federated States of Micronesia sparked public health concern. In 2013, the virus began to spread across other parts of Oceania and in 2015, a large outbreak in Latin America began in Brazil. Possible associations with microcephaly and Guillain-Barré syndrome observed in this outbreak have raised concerns about continued global spread of Zika virus, prompting its declaration as a Public Health Emergency of International Concern by the World Health Organization. We conducted species distribution modelling to map environmental suitability for Zika. We show a large portion of tropical and sub-tropical regions globally have suitable environmental conditions with over 2.17 billion people inhabiting these areas. Zika virus is transmitted between humans by mosquitoes. The majority of infections cause mild flu-like symptoms, but neurological complications in adults and infants have been found in recent outbreaks. Although it was discovered in Uganda in 1947, Zika only caused sporadic infections in humans until 2007, when it caused a large outbreak in the Federated States of Micronesia. The virus later spread across Oceania, was first reported in Brazil in 2015 and has since rapidly spread across Latin America. This has led many people to question how far it will continue to spread. There was therefore a need to define the areas where the virus could be transmitted, including the human populations that might be risk in these areas. Messina et al. have now mapped the areas that provide conditions that are highly suitable for the spread of the Zika virus. These areas occur in many tropical and sub-tropical regions around the globe. The largest areas of risk in the Americas lie in Brazil, Colombia and Venezuela. Although Zika has yet to be reported in the USA, a large portion of the southeast region from Texas through to Florida is highly suitable for transmission. Much of sub-Saharan Africa (where several sporadic cases have been reported since the 1950s) also presents an environment that is highly suitable for the Zika virus. While no cases have yet been reported in India, a large portion of the subcontinent is also suitable for Zika transmission. Over 2 billion people live in Zika-suitable areas globally, and in the Americas alone, over 5.4 million births occurred in 2015 within such areas. It is important, however, to recognize that not all individuals living in suitable areas will necessarily be exposed to Zika. We still lack a great deal of basic epidemiological information about Zika. More needs to be known about the species of mosquito that spreads the disease and how the Zika virus interacts with related viruses such as dengue. As such information becomes available and clinical cases become routinely diagnosed, the global evidence base will be strengthened, which will improve the accuracy of future maps.

Ebola virus disease (EVD) is a complex zoonosis that is highly virulent in humans. The largest recorded outbreak of EVD is ongoing in West Africa, outside of its previously reported and predicted niche. We assembled location data on all recorded zoonotic transmission to humans and Ebola virus infection in bats and primates (1976–2014). Using species distribution models, these occurrence data were paired with environmental covariates to predict a zoonotic transmission niche covering 22 countries across Central and West Africa. Vegetation, elevation, temperature, evapotranspiration, and suspected reservoir bat distributions define this relationship. At-risk areas are inhabited by 22 million people; however, the rarity of human outbreaks emphasises the very low probability of transmission to humans. Increasing population sizes and international connectivity by air since the first detection of EVD in 1976 suggest that the dynamics of human-to-human secondary transmission in contemporary outbreaks will be very different to those of the past. Since the first outbreaks of Ebola virus disease in 1976, there have been numerous other outbreaks in humans across Africa with fatality rates ranging from 50% to 90%. Humans can become infected with the Ebola virus after direct contact with blood or bodily fluids from an infected person or animal. The virus also infects and kills other primates—such as chimpanzees or gorillas—though Old World fruit bats are suspected to be the most likely carriers of the virus in the wild. The largest recorded outbreak of Ebola virus disease is ongoing in West Africa: more people have been infected in this current outbreak than in all previous outbreaks combined. The current outbreak is also the first to occur in West Africa—which is outside the previously known range of the Ebola virus. Pigott et al. have now updated predictions about where in Africa wild animals may harbour the virus and where the transmission of the virus from these animals to humans is possible. As such, the map identifies the regions that are most at risk of a future Ebola outbreak. The data behind these new maps include the locations of all recorded primary cases of Ebola in human populations—the ‘index’ cases—many of which have been linked to animal sources. The data also include the locations of recorded cases of Ebola virus infections in wild bats and primates from the last forty years. The maps, which were modelled using more flexible methods than previous predictions, also include new information—collected using satellites—about environmental factors and new predictions of the range of wild fruit bats. Pigott et al. report that the transmission of Ebola virus from animals to humans is possible in 22 countries across Central and West Africa—and that 22 million people live in the areas at risk. However, outbreaks in human populations are rare and the likelihood of a human getting the disease from an infected animal still remains very low. The updated map does not include data about how infections spread from one person to another, so the next challenge is to use existing data on human-to-human transmission to better understand the likely size and extent of current and future outbreaks. As more people live in, and travel to and from, the at-risk regions than ever before, Pigott et al. note that new outbreaks of Ebola virus disease are likely to be very different to those of the past.