The generation of a lactate-rich environment stimulates cell cycle progression and modulates gene expression on neonatal and hiPSC-derived cardiomyocytes

Ordoño, Jesús; Pérez‐Amodio, Soledad; Ball, Kristen; Aguirre, Aitor; Engel, Elisabeth

doi:10.1016/j.bioadv.2022.213035

Cited by 13 publications

(16 citation statements)

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“…In this sense, the most effective regeneration was found to be the one in which exogenous lactate was applied in the first 1−2 weeks after damage. 13 However, the effectivity of the proteinase K in the first week was very limited, the percentage of release due to the action of the enzyme being only 2% (x = 5.2), 6% (x = 26), and 6% (x = 52). On the other hand, Figure 7d−f shows that although the degradation of the plasma-treated PLA fibers had not finished after 29 days, the rate of degradation decreased after 20 days, slowing down the sustained release of lactate.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Adapting the Release to Heart Tissue Regeneration Requirements. Engel and co-workers 13 showed that a 6 mM daily dose of exogenous lactate over a period of 1 or 2 weeks increases the cardiac cell activity and metabolism, which promotes heart tissue regeneration in human IPS cells. The requirements for postnatal mice cardiomyocytes are set around 20 mM.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Based on such observations, those authors concluded that the use of exogenous lactate, released in a controlled manner from specifically designed smart platforms, could be a novel approach for cardiac tissue regeneration. 13 However, the number of studies aimed at developing smart platforms for the controlled release of lactate is very low, which is ascribed to its past consideration as metabolic waste as well as the fact that its clinical and biomedical functions have been only recently studied. A few early studies reported the release of lactate from the mucoadhesive vaginal gel 14 and from the Matrigel, 15 which is a solubilized basement membrane matrix secreted by mice sarcoma cells, for vaginal treatment and to heal skin wounds, respectively.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In the case of biodegradable PLA, it was shown that fibers can be used for a sustained release of lactate. 17,18 Based on the above, we hypothesized that the combination of a lactate-loaded hydrogel and PLA micro/nanofibers in a single platform could achieve both the immediate and sustained, but at the same time, abundant release (i.e., around 6 mM per day 13 ) of exogenous lactate necessary for cardiac regeneration, as well as provide a support for cardiac cells. Although an immediate lactate delivery is not a problem, considering its hydrophilicity, releasing a sufficient amount of lactate in a sustained manner over a prolonged period (e.g.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Such an observation opened the door to new opportunities for engineering novel therapeutic strategies for treating cardiomyopathies resulting from heart failure. For instance, Engel and co-workers showed that exogenous lactate increased cardiomyocyte cell cycle activity, modulated the production of inflammatory cytokines on cardiac fibroblasts, and, in addition, improved ex vivo neonatal heart culture. Based on such observations, those authors concluded that the use of exogenous lactate, released in a controlled manner from specifically designed smart platforms, could be a novel approach for cardiac tissue regeneration …”

Section: Introductionmentioning

confidence: 99%

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Enzymatic Degradation of Polylactic Acid Fibers Supported on a Hydrogel for Sustained Release of Lactate

Colombi,

Macor,

Ortiz-Membrado

et al. 2023

ACS Appl. Bio Mater.

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The incorporation of exogenous lactate into cardiac tissues is a regenerative strategy that is rapidly gaining attention. In this work, two polymeric platforms were designed to achieve a sustained release of lactate, combining immediate and prolonged release profiles. Both platforms contained electrospun poly(lactic acid) (PLA) fibers and an alginate (Alg) hydrogel. In the first platform, named L/K(x)/Alg-PLA, lactate and proteinase K (x mg of enzyme per 1 g of PLA) were directly loaded into the Alg hydrogel, into which PLA fibers were assembled. In the second platform, L/Alg-K(x)/PLA, fibers were produced by electrospinning a proteinase K:PLA solution and, subsequently, assembled within the lactate-loaded hydrogel. After characterizing the chemical, morphological, and mechanical properties of the systems, as well as their cytotoxicity, the release profiles of the two platforms were determined considering different amounts of proteinase K (x = 5.2, 26, and 52 mg of proteinase K per 1 g of PLA), which is known to exhibit a broad cleavage activity. The profiles obtained using L/Alg-K(x)/PLA platforms with x = 26 and 52 were the closest to the criteria that must be met for cardiac tissue regeneration. Finally, the amount of lactate directly loaded in the Alg hydrogel for immediate release and the amount of protein in the electrospinning solution were adapted to achieve a constant lactate release of around 6 mM per day over 1 or 2 weeks. In the optimized bioplatform, in which 6 mM lactate was loaded in the hydrogel, the amount of fibers was increased by a factor of ×3, the amount of enzyme was adjusted to 40 mg per 1 g of PLA, and a daily lactate release of 5.9 ± 2.7 mM over a period of 11 days was achieved. Accordingly, the engineered device fully satisfied the characteristics and requirements for heart tissue regeneration.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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