Engineered Stem Cells Survive Longer and Improve Outcomes in a Heart Patch

In most cell therapies, the transplanted cells do not survive for long, or in large numbers. They produce beneficial effects, such as reduced inflammation or enhanced regeneration, via signaling that changes the behavior of native cell populations. Considerable effort is going into finding ways to make cells used in therapy survive for a longer period of time following transplantation. The approach taken here is to engineer a fraction of the transplanted cells to produce a growth factor that improves the survival of the others. The results are demonstrated in an animal model, showing a greater regeneration of heart muscle.

Human mesenchymal stem cells (hMSCs) have been considered as one of the most promising cell sources for cell-based cardiac regeneration therapy because of their proven safety and notable paracrine effects to secrete numerous antiapoptotic and angiogenic growth factors, which enabled them to be a more competitive agent for clinical applications. However, unlike promising results obtained from preclinical models of myocardial infarction (MI), recent multiple meta-analyses have debated whether the therapeutic potential of hMSC treatment is sufficient. While these clinical trials successfully demonstrated the feasibility and safety of hMSC treatment, the researchers were unable to show significant functional benefit.

In response, diverse approaches have been attempted to enhance the therapeutic efficacy of hMSCs in treating MI. For instance, genetically engineered hMSCs overexpressing a number of antiapoptotic proteins, growth factors, or prosurvival genes - such as vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), and hepatocyte growth factor (HGF) - showed increased survival and retention in vivo resulting in improved cardiac function and myocardial angiogenesis in MI-induced hearts. However, these approaches require genetic modification and, therefore, are incompatible with clinical applications.

Another strategy to bolster the therapeutic potential of hMSCs is priming/preconditioning the hMSCs - which exposes them to physical treatments (e.g., hypoxia and heat shock), pharmacological agents, growth factors, distinct types of biomaterials, modified culture conditions, or other various molecules, including microRNAs - in vitro before transplantation into the hearts. However, it appears that the priming application only provides a short-term benefit.

Consequently, for hMSCs to be used more effectively for comprehensive cardiac repair, an innovative method that can maintain the priming effect of hMSCs more consistently and effectively must be developed. In the present study, we sought to develop a strategy, namely, in vivo priming, which could prime hMSCs in intact hearts in vivo. To induce and maintain the beneficial effects of priming persistently in situ, we loaded MSCs isolated from human bone marrow (BM-MSCs) together with genetically engineered HGF-MSCs (HGF-eMSCs) that continuously secrete HGF within a three-dimensional (3D) cardiac patch, which was implanted in the epicardium of MI-induced hearts. Subsequently, we demonstrated that the primed BM-MSCs had a higher survival rate compared with unprimed BM-MSCs in the patches while they were attached to the MI hearts, which led to a significant improvement in cardiac function and an enhancement of vessel formation after MI.



What is wrong with stem cells ? I heard about them for like 20 years and it's like almost no progress is made. What is the real problem to translate to real clinical therapies ? Is it only because they don't survive enough to make long-term beneficial effects ?

Posted by: Jonathan Weaver at April 7th, 2020 7:05 AM

@Jonathan Weaver: Agree. I remember when they were discovered in 98. Much opposition. We lost nearly a decade because of that. From 2008-2020 there have happened something but much less then I would like to see. Speak about it to family, friends. There should be more funds. Stop to vote in dumb politicians.

Posted by: thomas.a at April 7th, 2020 10:03 AM

@Thomas, you can blame Bush junior for stopping any embryonic stem cells research due to ethical issues during the early 00's:(

Posted by: Robert at April 7th, 2020 12:24 PM

"What is wrong with stem cells ? I heard about them for like 20 years and it's like almost no progress is made. What is the real problem to translate to real clinical therapies ? Is it only because they don't survive enough to make long-term beneficial effects ?"

It's because medical research isn't like tech. The experiments we do take years to decades, there are necessarily high standards for things to be tested in humans, and despite all our progress much of biology remains poorly understood. Stem cells also have an additional problem of cost, a cell therapy is inherently very, very expensive compared to a small molecule or biologic intervention.

Then there's the problem of how one gets stem cells to integrate into aged tissue and behave the way we would like them to; progress has been made there, examples being things like the stem cell heart patch.

Posted by: Dylan Mah at April 7th, 2020 2:00 PM
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