A study has demonstrated the first successful utilization of a photosynthetic system as a means of correcting tissue ischemia.
The Synechococcus elongatus ( S. elongatus ) use interstitial H2O and CO2 released by the oxygen-depleted cell and convert it to glucose and O2 with light serving as the energy source.
Glucose produced by S. elongatus is retained by the cyanobacterium themselves and likely does not benefit ischemic cardiomyocytes; however, oxygen levels are significantly increased.
By helping balance a pathologically unbalanced equation, cardiomyocytes are protected, translating to improved cardiac function.
The data have shown that S. elongatus can be efficiently used, allowing for direct delivery to ischemic myocardium. This treatment resulted in augmented tissue oxygenation, increased myocardial surface temperature likely secondary to metabolic activity, and greatly enhanced left ventricular function in an ischemic setting.
Although the absolute increase in CO in S. elongatus ( light ) injections compared to the S. elongatus ( dark ) injections seems relatively small and is somewhat variable, on average, it resulted in a nearly 30% increase in CO.
In humans, an increase of this magnitude would have profound clinical implications, likely representing the difference between a healthy patient and one suffering from heart failure.
Immunologic analysis demonstrated no obvious inflammatory response to the therapy. After intravenous delivery of 5 × 108 S. elongatus cells, blood cultures remained negative and the animals showed no clinical signs of infection for the duration of the 1-week observation period.
The persistence of S. elongatus in the tissue is likely short-lived, with most of the injected cells cleared from the tissue by 24 hours.
As such, this proposed therapy holds most potential in situations where a temporary supply of oxygen is required, such as during acute myocardial infarction before revascularization.
Increased tissue oxygenation forms the basis for enhanced myocardial bioenergetics. By allowing aerobic respiration to occur, adenosine triphosphate production is greatly enhanced, whereas lactic acid release is mitigated with the decrease in anaerobic glycolysis.
Clinically, this principle is used universally as providers strive to revascularize ischemic myocardium as quickly as possible in the setting of a myocardial infarction.
In this model, by quickly restoring oxygenation after an acute left anterior descending artery ( LAD ) occlusion, the heart has demonstrated increased metabolic activity and improved ventricular function.
Using S. elongatus to mitigate acute tissue ischemia has a range of possibilities, including its use as an adjunctive cardioplegia during cardiopulmonary bypass surgery or as a transplant organ perfusate to provide tissue with oxygen in the absence of blood flow during transport.
In addition to restoring oxygenation during ischemia, S. elongatus therapy may also exert beneficial effects after the restoration of blood flow. It has been demonstrated that, even after revascularization with coronary artery bypass grafting or percutaneous coronary intervention, a significant residual microvascular perfusion deficit remains. This leads to progressive ventricular remodeling, ischemic cardiomyopathy, heart failure, and death, which many survivors of acute myocardial infarction will eventually succumb to.
Angiogenic cytokine and stem cell–based therapies have been studied to address these issues; however, these treatments can take days to weeks to induce a substantial therapeutic response, potentially limiting the amount of myocardium that can be salvaged.
S. elongatus, either alone or as an adjunct to cell or cytokine therapies, may be an effective means of addressing microvascular disease and mitigating the development of the late ischemic cardiomyopathy.
Ischemia-reperfusion experiments support the fact that this strategy may be effective and translatable.
Researchers have demonstrated that 2 hours of active therapy while the heart was exposed to light resulted in significant functional benefits and preserved ventricular architecture 4 weeks later. These benefits are presumably due to increased tissue oxygenation during the period of hypoxia, allowing a greater number of cells to survive until blood flow is restored.
Although it is possible that the cyanobacteria alleviate microvascular perfusion deficits after reperfusion, resulting in additional benefits, it is not possible to quantify this with certainty; this is a limitation of the study.
Despite these limitations, the observed benefits do have significant clinical implications, indicating that S. elongatus therapy could be used as an immediate adjunct to current medical interventions for patients suffering an acute myocardial infarction.
A limiting factor to this particular application is the need for the tissue to be in direct light, necessitating an open incision for the delivery of photons, because most cases of acute myocardial infarction are treated in the cardiac catheterization suite.
However, recently, a new chlorophyll pigment, chlorophyll f, that absorbs light in the infrared spectrum, was identified in other cyanobacteria; using a strain of cyanobacteria active in the far-red spectrum could potentially allow for transcutaneous delivery of energy.
Combining transcutaneous energy delivery with percutaneous or intracoronary administration of S. elongatus would be a promising step toward human translation.
Genetically engineering S. elongatus to actively export glucose has been described. S. elongatus produces intracellular sucrose to balance osmolarity in its saltwater environment; this feature can be exploited to create a strain of S. elongatus that produces and exports high levels of carbohydrates.
By using homologous recombination, the Zymomonas mobiles invA gene that codes for invertase can be introduced, which allows intracellular sucrose to be cleaved into fructose and glucose before being actively extracellularly exported along with the glf gene encoding a glucose / fructose-facilitated diffusion transporter.
Extracellular sodium chloride concentration can then be manipulated to adjust the amount of glucose produced.
Researchers have preliminarily explored this technique, creating a plasmid containing these genes and creating an enhanced glucose producing strain of S. elongatus through transformation with some early success.
This avenue of research could substantially improve the efficacy of cyanobacterial therapy and bring the technology closer to clinical translation.
Although extremely different from any known strategy addressing myocardial ischemia, the use of S. elongatus to provide ischemic cardiomyocytes with oxygen via photosynthesis represents a novel and potentially feasible approach to treating the ischemic heart.
Because S. elongatus is amenable to genetic engineering, there are countless possibilities regarding the augmentation of energy production, in vivo tracking, and growth control.
Although obstacles exist, as with any new therapy in its infancy, the data suggest a very real benefit from the use of photosynthesis to treat ischemic disease. ( Xagena )
Source: Science, 2017