Cardiovascular organoids

While cardiovascular diseases remain the leading cause of death worldwide, it has been progressively acknowledged that incorrect recapitulation of the pathogenesis of human diseases by animal (more specifically mammal) models, together with their significant cost and limited throughput, significantly contribute to the failure in providing human-relevant insights into disease mechanisms and in translating novel therapies to the clinic. A partial solution to these drawbacks is currently being explored by inducing human cells to differentiate and self-organize in vitro into 3D structures that structurally and functionally resemble a specific organ, i.e. organoids. The field of cardiovascular (CV) research has embraced this recent and promising technology. Accordingly, attempts are being made to develop CV organoids from both the myocardial and vascular perspectives. An additional incentive for the specific development of complex blood vessel organoids (BVO) is that those may benefit to the whole field of organoid research considering that the integration of a functional vasculature into organoids of any given tissue would overcome the limits of organoid perfusion using microfluidic chips and would greatly enhance the relevance of the whole technology.

The team of Josef Penninger has been and still is pioneering the development of a faithful human BVO based on the differentiation of mesodermal progenitors. ,  The authors thus described for the first time a self-organizing human capillary network consisting in endothelial cells, pericytes, mesenchymal stem-like cells, and a very small percentage of hematopoietic cells. Salewskij & Penninger very recently provided an excellent state-of-the-art review of the emerging field of BVOs, from which we hope this commented paper will inspire further reading.  Starting from basic, 2D in vitro monolayer cultures of human vascular (mainly endothelial) primary cells, the authors go all the way to the most recent studies describing the implant of BVO into immunodeficient mice allowing the preclinical availability of a fully perfused human vascular tree. They also highlight the limitations of such models in terms of throughput, a parameter that, as mentioned above, was itself the driving force behind the development of BVOs.

While Salewskij & Penninger emphasize that BVOs have been shown to be amenable to model physiopathologic processes occurring in diabetic vasculopathy, that they successfully recapitulate normal human microvasculature features from a metabolic perspective, and that they recently provided insights into the consequences of altered glycolytic metabolism on microvascular integrity, they do not on the other hand hesitate to point to the great amount of work that remains to be performed prior to reaching larger and more complex arteriole- or venule-like BVO. Indeed, currently available BVOs do not possess medial and adventitial layers, thereby limiting their applicability to the study of atherosclerotic processes. In addition, BVO perfusion remains a challenge, and current research is also focusing on establishing perfusion using advanced microfluidics in order to obtain large and complex BVO without the need for in vivo animal transplantation as mentioned above.

The field is also in its infancy with regards to the potential of BVO for the study of coronary microvascular dysfunction (CMD). Indeed, and to the best of our knowledge, the use of currently available BVOs for the study of CMD has been mentioned as a potentiality by some,  but it likely waits for the development of larger and more complex microvessel-like BVO to be practically implemented. Overall, the review by Salewskij & Penninger provides a timely and highly interesting state-of-the-art of the BVO field, which will undoubtedly contribute to providing significant and directly human-relevant fundamental insights into CMD, as well as serving as a high-throughput modality for drug screening in the years to come.