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Encapsulated Stem Cells Improve Heart Regeneration

Researchers here report on a cheaper implementation of encapsulation for transplanted stem cells, preventing the recipient's immune system from attacking cells originating from a different individual or even different species. Since the stem cells produce improvement in regeneration in heart tissue via signaling, there is no need to expose the cells themselves to the local environment - the cells are only needed at all because the signaling environment is not yet fully mapped and understood. Encapsulating transplanted cells in a nanogel extends their lifetime and thus the therapeutic effect.

As a promising approach to tissue repair, multiple types of stem cells have entered the stage of clinical testing. However, their efficacy is limited by low retention and engraftment of transplanted cells, together with the potential risk of inflammation and immunoreaction when allogeneic or xenogeneic cells are used. Heart diseases including myocardial infarction (MI) and heart failure remain the leading cause of death worldwide. Even with the most advanced pharmacological and medical device treatment methods, mortality and morbidity of heart disease stay high. Cardiac tissue engineering and stem cell transplantation approaches aim at de novo cardiac regeneration after injury. Clinical outcomes of cardiac stem cell (CSC) therapy are hampered by low cell retention rate and side effects associated with immune rejection if allogeneic cells are used.

Injectable hydrogels have been used to treat MI, and the studies have been demonstrated to improve cardiac function via increased heart wall thickness and reduced wall stress. Various natural polymers such as fibrin, collagen, Matrigel, chitosan, keratin, and hyaluronic acid have been investigated as injectable hydrogels to treat MI. They have excellent biocompatibility and can promote cell migration, proliferation, and/or differentiation, leading to ultimate heart regeneration/repair. However, the drawbacks of natural polymers hampering their clinical applications are their batch-to-batch variation and expensive cost.

Synthetic polymers hold the potential to replace natural polymers as injectable hydrogels to treat MI. One appealing regenerative medicine strategy for MI is encapsulating stem cells such as CSCs inside the hydrogels and deliver the cell-laden hydrogels into the damage tissues. Here, we propose the use of P(NIPAM-AA) nanogel, a synthetic injectable carrier to encapsulate human CSCs in mouse and pig models of MI. The nanogel serves as a scaffolding material to enhance cell retention and as a barrier to prevent T cells from entering and attacking the encapsulated CSCs. The treatment ultimately resulted in augmented cardiac function and stimulation of endogenous regeneration.

The mechanisms underlying the therapeutic benefits of nanogel-encapsulated CSC therapy are likely to be complicated. Our findings indicated that the P(NIPAM-AA) nanogel-encapsulated hCSCs promoted post-MI cardiac repair by the inhibition of apoptosis and promotion of angiomyogenesis. Collectively, these favorable actions lead to reduced fibrosis and improved cardiac function. Fast degrading natural polymers do not support long-term support to the heart. In contrast, synthetic polymers cannot be quickly removed by enzyme activities. In real scenarios, we expect the nanogel will provide a shield for allogeneic stem cells or induced pluripotent cells, which are likely to trigger immune reaction in the host tissue. In addition, the polymer carrier can drastically improve cell retention rate.

Link: https://doi.org/10.1021/acsnano.7b01008

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