A mechanistic roadmap for the clinical application of cardiac cell therapies

Abstract

The development of cells for regenerative therapy has encountered many pitfalls on its path to clinical translation. In cardiology, clinical studies of heart-targeted cell therapies began two decades ago, yet progress towards reaching an approved product has been slow. In this Perspective, I provide an overview of recent cardiac cell therapies, with a focus on the hurdles limiting the translation of cell products from research laboratories to clinical practice. By focusing on heart failure as a target indication, I argue that strategies for overcoming limitations in clinical translation require an increasing emphasis on mechanism-supported efficacy, rather than on phenomenological observations. As research progresses from cells to paracrine mechanisms to defined factors, identifying those defined factors that are involved in achieving superior therapeutic efficacy will better inform the use of cells as therapeutic candidates. The next generation of cell-free biologics may provide the benefits of cell therapy without the intrinsic limitations of whole-cell products.

Fig. 1 |. Biological processes modulated by cell therapy.

The direct progeny of transplanted cells can generate new heart muscle and blood vessels by canonical mechanisms. Yet other biological processes may be stimulated or suppressed via non-canonical (indirect) mechanisms of cell action.

Fig. 2 |. Clinical testing of cell therapies for heart disease.

Cell types that are actively being studied are depicted as boxes with an open righthand edge. Cell types in fully enclosed boxes represent programmes that no longer seem in active clinical development since the time of the last reported trial. The thickness of the triangles is roughly proportional to the number of trials conducted at each time point; phase-I trials are depicted in blue, and phase-II and later trials in red. ESCs, embryonic stem cells.

Fig. 3 |. Obstacles in the translation of cell therapy, from proof of concept through to product approval.

The process is akin to navigating a maze, with obstacles including legacy concerns introduced by a history of unsound scientific practices and relentless hype; the transition from small-scale phase-I manufacturing to commercial-scale manufacturing introduces the potential for product drift, lack of reproducibility of key product characteristics, difficulties establishing mechanistically based potency assays, and concerns related to safety.

Fig. 4 |. CDC properties.

The approach for specimen processing for CDC growth and expansion. Figure adapted from ref. , Wolters Kluwer Health, Inc.

Fig. 5 |. Changes from canonical to indirect (paracrine) mechanisms of action of cell therapy.

Diagram based on evidence provided in refs ^,,,–.

Fig. 6 |. Exosome biology and evidence of exosome efficacy.

a, Schematic of exosome biogenesis and release. (1) Exosome payload, including proteins and RNA, are synthesized in the nucleus and matured in the endoplasmic reticulum. (2) Sorting occurs in the trans-Golgi system (shown in red), where exosome signals are labelled with ceramide and with trafficking proteins that mediate budding into the endosome. (2’) The endosome itself is a product of invagination of the plasma membrane. Intraluminal vesicles form by fusion with the endosome, and acquire surface-marker profiles that are conserved. The markers include tetraspanins and heat-shock proteins, as well as markers specific to the parent cell. (3) The multivesicular body progressively acidifies, which leads to fusion with the plasma membrane and the release of intraluminal vesicles (exosomes). nSMase, neutral sphingomyelinase. b, Blockade of CDC exosome biosynthesis with the small molecule GW4869 undermines CDC efficacy in improving heart function after myocardial infarction (MI). c, CDC exosomes mimic the functional benefits of CDCs after MI. LVEF, left ventricular ejection fraction. Panels b and c adapted from ref. , Elsevier.

Fig. 7 |. Defined exosome contents implicated in cdc-mediated cardioprotection.

Left: biogenesis and secretion of exosomes. Right: exosome contents. lncRNA, long non-coding RNA; miRNA, microRNA; IL-10, interleukin 10; PKCδ, protein kinase C isoform; TRAF-6, tumour necrosis factor receptor- associated factor 6. Figure adapted from ref. , Elsevier.