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World J Stem Cells. 2022 Jan 26; 14(1): 140.

Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt. ge.ude.demxela@annahem.awdar

Radwa A Mehanna, Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt;

Supported by Science and Technology Development Fund, No. 28932; and Cardiovascular Research, Education, Prevention Foundation, CVREP - Dr. Wael Al Mahmeed Grant.

Corresponding author: Radwa A Mehanna, MD, PhD, Academic Research, Professor, Executive President, Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Al Khartoum Square, Azareeta, Alexandria 21500, Egypt. ge.ude.demxela@annahem.awdar

Received 2021 Feb 26; Revised 2021 Jul 2; Accepted 2022 Jan 6.

Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.

Keywords: Cardiac stem and progenitor cells, Cardiac stem cells secretome, Cardiac stem cells niche and metabolism, Nanotechnology, Clinical trials, Combined therapy

Core Tip: With the growing evidence for the existence of regenerating cardiac stem and progenitor cells, studies to evaluate their therapeutic potential have received increasing attention. Although pre-clinical research and clinical trials have demonstrated promising results, yet the latter were often inconsistent in many aspects thus imposing the need for deeper exploration of the molecular biology and relevant pathways regulating cardiogenesis and cardiac muscle repair. This review gives an insight into cardiac stem and progenitor cells regarding their embryological origin, populations, niche, secretome, and metabolism. It overviews the current preclinical research, including medical nanotechnology, and the clinical trials generally applied for cardiac regeneration.

Cardiovascular diseases are the leading cause of death globally, as stated by the latest report 2019 for the World Health Organization, with 17.9 million deaths per year, accounting for 31% of all deaths worldwide.

The heart is one of the least proliferative organs in the human body, and its minimal regenerative capacity has been dogma for decades. Such dogma has been led by the belief that the heart cannot regenerate from ischemic damage. The absence of primary tumors in the heart has further supported the notion of low proliferation. In an alleged post-mitotic organ, it has been debatable whether cardiac cells repair through activation of resident cardiac stem cells (CSCs) and cardiac progenitor cells (CPCs) or by the proliferation of pre-existing cardiomyocytes (CMs). In 2009, Bergmann et al[1] were the first to refute that notion and have reported that the heart can in fact self-renew. Based on the results obtained from their carbon-14-labelled DNA study to track CMs, Bergmann et al[1] stated that about 50% of CMs renew over the lifespan of an adult. Hsieh et al[2] provided further evidence for the origin of newly generated CMs from progenitor cells in an alpha myosin heavy chain (MHC) transgenic model. They estimated that approximately 15% of CMs can regenerate in adult hearts following ischemic damage. With progression of research, lineage tracing of regenerated cardiac tissue confirmed that the newly regenerated CMs develop from a non-CM and possibly from stem cells (SCs)[2].

Further studies have revealed various CSC/CPC candidates that are morphologically and functionally distinct from each other yet act in a complementary fashion and contribute to the regeneration process. This complex cell aggregation is known as the CSC niche that has been a challenge to characterize and locate anatomically[3].

SC applications have been under intensive research interest since the early 20th century. Many types have been isolated, starting from the embryonic, amniotic, and cord blood mesenchymal stem cells (MSCs) and passing through the adult SCs till the induced pluripotent SCs (iPSCs). Adult MSCs are undifferentiated cells with the same potentials as progenitor cells regarding the ability to differentiate into all three germ layer cells[4]. Exogenous MSCs from various sources, including bone marrow, adipose tissue, umbilical cord, placenta, and amniotic fluid[5], have shown promising results in the treatment of cardiovascular diseases. However, the outcome of CSC therapy has shown superior results in experimental studies but to a lesser extent in human clinical trials[6]. The applications of SC therapy for cardiovascular regeneration still hold a plethora of queries to be answered as well as commandment of the molecular and signaling features for CSCs in order to standardize this therapy. Among the aspects that need optimization are the types of SCs and supporting cells to be used, the number of cells, the route of injection, the frequency, and best timing for transplantation. Standardization requires an advanced understanding of the full biological features of CSCs.

SC therapy in cardiac regeneration has dual beneficiary actions. Primarily, the transplanted exogenous SCs would directly differentiate into CMs. Concomitantly, SCs activate the endogenous progenitors through their rich secretome of extracellular vesicles, immunomodulatory and growth factors, protein, and nucleic acid families[7]. These paracrine factors act to activate resident SCs and enhance vascularization to potentiate cardiac repair.

This review aims to provide insight into CSCs/CPCs regarding their embryological origin, populations, niche, metabolism, secretome, and therapeutic potentials. Also discussed is the interplay of nanotechnology with SCs in several aspects, including differentiation, tracking, imaging, and assisted therapy, showing the prospects and limitations of nanoparticle (NP)-based cardiac therapy. Finally, preclinical trials and ongoing, completed, and future clinical trials using CSCs and combined therapy are shown to delineate the potential applications in treating cardiac disease.

The heart is formed of a wide range of cell types originating from the mesodermal precursor cells. They include CMs and endocardial cells forming the inner layer, while epicardial-derived cells (EPDCs) and smooth muscle cells (SMCs) are found on the external layer. Differentiation of the mesodermal cells is initiated by the T-box transcriptional factors Brachyury (Bry) and Eomes. Bry+ cells differentiate into insulin gene enhancer protein islet-1 (ISL1) and T-box transcription factor 5 (TBX5) expressing cells, while Eomes induce expression of mesoderm posterior 1 (MESP1). MESP1+ cells are identified before the first heart field (FHF) and the second heart field (SHF) separations, so MESP1 serves as an indicator of early CPCs for both heart fields[8]. Chemokine receptor type 4 (CXCR4), fetal liver kinase 1 (FLK-1), and platelet derived growth factor receptor A are other surface markers that coincide with MESP1 and are used in combination to isolate CPCs[9,10].

In addition, a novel cell surface marker known as G protein-coupled receptor lysophosphatidic acid receptor 4 is specific to CPCs and determines its functional significance. Interestingly, its transient expression peaks in cardiac progenitors after 3 to 7 d of human (h)PSCs differentiation toward cardiac lineage, then it declines. In vivo, lysophosphatidic acid receptor 4 shows high expression in the initial stages of embryonic heart development and decreases throughout development[11].

The FHF cells are the firstly differentiated myocardial cells that are derived from cells in the anterior lateral plate mesoderm; they give rise to the left ventricle, partially some of the right ventricle population, sinoatrial node, atrioventricular node, and both atria[12]. Meanwhile, the SHF cells originate from the pharyngeal mesoderm to the posterior side of the heart and further divide into anterior and posterior SHF. They contribute to the right ventricle, atria, and the cardiac outflow tract (OFT) formation. Addition of the SHF-derived CMs to the ventricles depend on myocyte enhancer factor 2C (MEF2C). It has been found that MEF2C null mice die at 9.5-d post conception with severe heart defects due to failure of heart looping[13]. In OFT formation, two waves of SHF progenitors and their derivatives have been identified, making a differential contribution to the aorta and pulmonary artery. The early wave of cells is favorably directed to the aorta, while the second wave of cells contributes to the pulmonary artery. Phosphoinositide-dependent kinase-1 critically regulates the second wave of cells, and its deletion results in pulmonary stenosis[14]. The epicardium of the heart is formed of a transient proepicardial organ. Proepicardium is formed from homeobox protein NKx2.5 (NKx2.5) and ISL1+ cells. After epicardial formation, subepicardial mesenchymal space is formed by epithelial to mesenchymal cell transformation of the epicardial cells[15] (Figure ).

Embryonic cardiac progenitors, Brachyury-positive mesoderm precursors and Pax3+ neural crest cells. Brachyury (Bry+) mesoderm precursors give rise to the mesoderm posterior 1+ primordial precursors, which are the origin of the first heart field, second heart field, and proepicardial progenitors, each population of which is responsible for the development of different parts in the heart. Pax3+ neural crest cells are responsible for the development of vascular smooth muscle, outflow tract, valves and the conductive system. Progenitors are tagged with their specific markers. Created with BioRender.com. CPC: Cardiac progenitor cell; LT: Left; RT: Right; FHF: First heart field; SHF: Second heart field; OFT: Outflow tract.

The differentiation in the posterior SHF is regulated by Hoxb1 gene. Stimulation of Hoxb1 in embryonic stem cells (ESCs) halts cardiac differentiation, while Hoxb1-deficiency shows premature cardiac differentiation in embryos. Moreover, an atrioventricular septal defect develops as a result of ectopic differentiation in the posterior SHF of embryos deficient in Hoxb1 and its paralog Hoxa1[16].

Multiple signaling pathways have essential roles in cardiogenesis with a sequential arrangement. The transforming growth factor- (TGF-) superfamily, retinoic acid, Hedgehog, Notch, Wnt, and fibroblast growth factors (FGFs) pathways comprise the chief signaling pathways involved in cardiac development. These pathways, along with transcription factors and epigenetic regulators, regulate cardiac progenitors specification, proliferation, and differentiation into the different cardiac cell lineages[17].

The TGF- superfamily members consist of over 30 structurally associated polypeptide growth factors including nodal and bone morphogenetic proteins (BMP)[18].

Nodal signaling is vital for the formation of sinoatrial node. Nodal inhibition during the cardiac mesoderm differentiation stage downregulates PITX2c, a transcription factor recognized to inhibit the formation of the sinoatrial in the left atrium during cardiac development[19]. Moreover, nodal signaling is dispensable for initiation of heart looping; however, it regulates asymmetries that result in a helical shape at the heart tube poles[20].

BMP signaling, as a member of TGF-, has an important role in the different stages of heart development including the OFT formation, endocardium, and lastly the epicardium. The cardiac neural crest cells have a crucial role in normal cardiovascular development. They give rise to the vascular smooth muscle of the pharyngeal arch arteries, OFT septation, valvulogenesis, and development of the cardiac conduction system[21] (Figure ). The role of BMP in OFT septation mainly depends on their gradient signaling, which arranges neural crest cell aggregation along the OFT; this Dullard-mediated tuning of BMP signaling ensures the fine timed zipper-like closure of the OFT by the neural crest cells[22]. Furthermore, the BMP signaling promotes the development of endocardial cells (ECs) from hPSC-derived cardiovascular progenitors[23]. It is also integrated with Notch signaling for influencing the proepicardium formation, where overexpression of Notch intracellular receptor in the endothelium enhances BMP expression and increases the number of phospho-Smad1/5+ cells for enhancing the formation of the proepicardium[24].

Retinoic acid signaling plays a role in heart development. It is a key factor for efficient lateral mesoderm differentiation into atrial-like cells in a confined time frame. The structural, electrophysiological, and metabolic maturation of CMs are significantly influenced by retinoic acid[25]. However, it is reported that retinoic acid receptor agonists transiently enhance the proliferation of human CPCs at the expense of terminal cardiac differentiation[26].

The downregulation of the retinoic acid responsive gene, ripply transcriptional repressor 3 (RIPPLY3), within the SHF progenitors by histone deacetylase 1 is required during OFT formation[27].

Hedgehog signaling has a role in OFT morphogenesis. Lipoprotein-related protein 2 (LRP2) is a member of the LDL receptor gene family, a class of multifunctional endocytic receptors that play crucial roles in embryonic development. LRP2 is expressed in the anterior SHF cardiac progenitor niche, which leads to the elongation of the OFT during separation into aorta and pulmonary trunk. Loss of LRP2 in mutant mice results in depleting a pool of sonic hedgehog-dependent progenitor cells in the anterior SHF as they migrate into the OFT myocardium due to premature differentiation into CMs. This depletion results in aberrant shortening of the OFT[28].

Four Notch receptors (Notch1Notch4) and five structurally similar Notch ligands [Delta-like (DLL) 1, DLL3, DLL4, Jagged1, and Jagged2] have been detected in mammals[29]. Activation of Notch signaling enhances CM differentiation from human PSCs. However, the CMs derived from Notch-induced cardiac mesoderm are developmentally immature[30]. In vivo, the Notch pathway plays a significant role in CPC biology. An arterial-specific Notch ligand known as DLL4 is expressed by SHF progenitors at critical time-points in SHF biology. The DLL4-mediated Notch signaling is a crucial requirement for maintaining an adequate SHF progenitor pool, in a way that DLL4 knockout results in decreased proliferation and increased apoptosis. Reduced SHF progenitor pool leads to an underdeveloped OFT and right ventricle[31].

The Wnt signaling pathway has an essential role in many developmental stages of embryogenesis. The Wnt family consists of 19 distinct Wnt proteins and other 10 types of Frizzled receptors. On the basis of their primary functions, the Wnt and Frizzled receptors are divided into two major classes, which are the canonical and non-canonical Wnt pathways[32]. Accumulating evidence suggests a role for the dynamic balance between canonical and non-canonical Wnt signaling in cardiac formation and differentiation. Wnt/-catenin signaling is required for proper mesoderm formation and proliferation of CMs but needs to be low for terminal differentiation and cardiac specification. In contrast, for cardiac specification in murine and human ESCs, non-canonical -catenin independent Wnt signaling is essential, while the non-canonical Wnt signaling is necessary for terminal differentiation later in development[33].

The activation of non-canonical Wnt is non-catenin-independent, and the downstream proteins involve several kinases, including protein kinase C, calcium/ calmodulin-dependent kinase, and Jun N terminal kinase (JNK). Wnt11 enhances angiogenesis and improves cardiac function through non-canonical Wnt-protein kinase C-Jun N terminal kinase dependent pathways in myocardial infarction (MI)[34]. In hypoxia, Wnt11 expression preserves the integrity of mitochondrial membrane and facilitates the release of insulin growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF), thus protecting CMs against hypoxia[35]. Canonical dependent Wnt signaling, Wnt 3 Ligand, favors the pacemaker lineage, while its suppression promotes the chamber CM lineage[36].

The regenerative capacity of most organs is contingent on the adult SC populations that exist in their niches and are activated by injury. Adult SC populations vary greatly in their molecular marker expression profile and hence in their possible role in regenerative medicine. The transcriptome is a representation of the gene read-outs, the cellular state, and is imperative for studying all genetic disease and biological processes. The genome-wide profiling using novel sequencing technology has made transcriptome research accessible.

Receptor tyrosine kinase (RTK) c-KIT (also referred to as SC factor receptor or CD117)-expressing CPCs are mainly located in the atria and the ventricular apex, comprising most of the ventricular and atrial myocardium[37]. c-KIT+ cells also express the cardiac transcription factors NKx2.5, GATA binding protein 4 (GATA4), and MEF2C but are negative for the hematopoietic markers CD45, CD3, CD34, CD19, CD16, CD20, CD14, and CD56[38,39]. SC factor ligand attaches to the c-KIT receptor and activates the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and p38 mitogen-activated protein kinase (MAPK) signaling pathways[40]. Both PI3K/AKT and MAPK pathways control various CPCs functions like self-renewal, proliferation, migration, and survival[41]. During embryonic development and the early post-natal time, c-KIT+ CPCs contribute to the generation of new CMs. Such capacity declines in the adult heart with only a few new CMs originating from CPCs[42]. In a rat MI model, the c-KIT+ CPCs have migrated through the collagen type I and type III matrices into the infarcted area. The transplanted CPCs have shown overexpressed matrix metalloproteinases (MMPs; MMP2, MMP9, and MMP14) that degrade extracellular matrix (ECM), concluding that c-KIT+ CPCs hold an invasive capacity[43]. Transplanted CPCs (c-KIT+ CPCs and cardiospheres) also show an endogenous proliferative potential in vivo and additionally activate endogenous CPCs[44].

Stem cell antigen 1 (SCA-1) expressing CPC population exists predominantly in the atrium, intra-atrial septum, and atrium-ventricular boundary and dispersed inside the epicardial layer of adult hearts[45]. SCA-1 is a cell surface protein of the lymphocyte antigen-6 (Ly6) gene family, which has roles in cell survival, proliferation, and differentiation[46]. A population of SCA-1+ cells from murine adult myocardium hold a telomerase activity comparable to that of a neonatal heart. This SCA-1+ population is different from hematopoietic SCs as they lack CD45, CD34, c-KIT, LIM domain only 2, GATA2, VEGF receptor 1, and T-cell acute lymphoblastic leukemia 1/SC leukemia proteins. SCA-1+ cells are also distinct from endothelial progenitor cells and express cardiac lineage transcriptional factors such as GATA4, MEF2C, and translation elongation factor 1 yet lack transcripts for cardiomyocytic structural genes such as BMP1r1 and -, -MHC[47,48]. Although this population exhibits the endothelial marker CD31, it is suggested to be due to the contaminating endothelial CD31+/SCA-1+ cells. In vitro studies have revealed that 5-azacytidine (5-aza), a demethylating agent, pushed SCA-1+ cells to differentiate into CMs[48,49]. Further studies have isolated SCA-1+ cells that lack CD31 and CD45 markers, referring to them as lineage negative (Lin). The SCA-1+/Lin cells display a mesenchymal cell-surface profile (CD34, CD29+, CD90+, CD105+, and CD44+) and are able to differentiate, to a certain extent, into CMs and endothelial and smooth muscle-like cells[50,51].

Human SCA-1+-like cells also express early cardiac transcription factors (GATA4, MEF2C, insulin gene enhancer protein ISL-1, and Nkx-2.5) and can differentiate into contractile CMs[52]. Although a human ortholog of the SCA-1 protein has not been yet identified, an anti-mouse SCA-1 antibody is used to isolate SCA-1+-like cells from the adult human heart.

MESP1 expressing cells mainly contribute to the mesoderm and to the myocardium of the heart tube during development[53]. Transient expression of MESP1 seems to accelerate and enhance the appearance of cardiac progenitor. However, homologous disruption of the MESP1 gene has resulted in aberrant cardiac morphogenesis. MESP1 interacts with the promoter area of main cardiac transcription factors, including heart and neural crest derivatives expressed 2, Nkx2-5, myocardin, and GATA4[54]. These factors induce fibroblasts to express a full battery of cardiac genes, form sarcomeres, develop CM-like electrical activity, and in a few cases elicit beating activity[55]. Several studies have shown that the addition of MESP1 could enhance the efficacy of direct reprogramming of fibroblasts into CMs[56,57]. The transdifferentiation of fibroblasts to CMs via MESP1 suggests that MESP1 chiefly modulates the gene regulatory network for cardiogenesis[52].

Kinase insert domain receptor (KDR), also known as Flk-1, is one of the earliest discovered cardiogenic progenitor cell markers acting during the early stages of cardiac development in human[58]. Nelson et al[59] have reported that Flk-1 has a distinctive transcriptome that has been evident at day 6, immediately after gastrulation but prior to the expression of the cardiac transcription factors. KDR+ population lack the pluripotent octamer-binding transcription factor 4, sex determining region Y-Box transcription factor (SOX) 2, and endoderm SOX17 markers. On the other hand, KDR+ CPCs have shown a noteworthy upregulation in SOX7, a vasculogenic transcription factor, overlapping with the emergence of primordial cardiac transcription factors GATA4, myocardin, and NKx2.5. Moreover, KDR subpopulations that overexpress SOX7 are associated with a vascular phenotype rather than a cardiogenic phenotype. These outcomes offer insights for refining the therapeutic regenerative interventions.

The FHF cells express hyperpolarization activated cyclic nucleotide gated potassium channel 4 and TBX5, while SHF progenitors express TBX1, FGF 8, FGF10, and sine oculis homeobox2 (Figure ). Cells from the SHF exhibit high proliferative and migratory capacities and are mostly responsible for the elongation and winding of the heart tube. Moreover, SHF cells differentiate to CMs, SMCs, fibroblasts, and endothelial cells (ECs) along their journey in the heart tube to form the right ventricle, right ventricular OFT, and most of the atria[60,61]. However, FHF cells hold less proliferative and migratory potentials and differentiate predominantly to CMs that form the left ventricle and small parts of the atria[62]. The cells of the cardiac crescent, theoretically the progeny of FHF CPCs, are terminally differentiated cells expressing the markers of CMs, such as actin alpha cardiac muscle 1 and myosin light chain 7[63,64], hence they are unlikely to be multipotent progenitors. Therefore, it is difficult to identify FHF before Nkx2.5 and TBX5 expressions. Conversely, multipotent SHF CPCs were validated with a clonal tracing experiment and identified by ISL1 expression[65]. However, ISL1 expression is not specific for SHF and has been proposed to represent only the developmental stages[66]. Tampakakis et al[67] generated ESCs by using hyperpolarization activated cyclic nucleotide gated potassium channel 4-green fluorescent protein and TBX1-Cre; Rosa-red fluorescent protein reporters of the FHF and the SHF respectively, and also by using live immunostaining of the cell membrane CXCR4, a SHF marker and the reporters. The ESC-derived progenitor cells have shown functional properties and transcriptome similar to their in vivo equivalents. Thus, chamber-specific cardiac cells have been generated for modelling of heart diseases in vitro.

The EPDCs are important as a signaling source for heart development, cardiac regeneration, and post-MI heart repair. Throughout the development of the heart in mice, EPDCs aid in the formation of various cardiac cell types and secrete paracrine factors for myocardial maturation[68]. In the adult heart, EPDCs are normally dormant and become stimulated following myocardial injury. Transcriptional analysis of the EPDCs derived from human (h)iPSCs cells have revealed several markers of EPDCs including Wilms tumor protein 1, endoglin, thymus cell antigen 1, and aldehyde dehydrogenase 1 family member A2[69] (Figure ). Following MI in mice, EPDCs undergo an epithelial-to-mesenchymal transition, with overexpression of Wilms tumor protein 1, and differentiate mainly into SMCs/fibroblasts[70,71]. EPDC-secreted paracrine factors include VEGF-A, FGF2, and PDGF-C, which support the growth of blood vessels, protect the myocardium, and recover cardiac functions in an acute MI-mouse model[70].

Side population (SP) cells have been detected in the heart and other various tissues and hold enhanced stem and progenitor cell activity[72]. SP cells, when stained in vitro, hold the ability to flush out the DNA Hoechst dye from their nuclei[73]. Gene expression profiling of SP cells after MI has revealed a downregulation of Wnt-related signals coupled with increased SP cell proliferation. This has been validated in vitro by treatment of isolated SP cells with canonical Wnt agonists or recombinant Wnt, where the proliferation of SP cells has been repressed with partial arresting the G1 cell cycle phase[74]. Consistent with this observation, delivery of secreted Frizzled-related proteins (SFRP; the Wnt antagonizer) improves post-MI remodeling[75,76].

SP cells can be identified by surface marker adenosine triphosphate (ATP) binding cassette subfamily G member 2 (ABCG2), also referred to as the breast cancer resistance protein1[77]. ABCG2+ cells have been also observed in the adult heart and can differentiate in vitro into CMs[78]. When SP cells have been injected into the injured hearts of rats, they have been recruited to the injured regions, where they differentiate into CMs, ECs, and SMCs, suggesting that they may be endogenous SP cells[79]. However, ABCG2CreER based genetic lineage tracing has demonstrated that ABCG2+ cells could only differentiate into the multiple cardiac cell lineages during the embryonic stages but not in adulthood[80,81]. The combination of ABCG2+ cells with pre-existing CMs is more likely to stimulate CM proliferation rather than differentiation into CMs directly[82]. Therefore, genetic fate mapping investigations have disproved the SP cells property of the adult endogenous ABCG2+ SP and their in vivo renewing myogenic ability[83].

Cardiospheres contain a combination of stromal, mesenchymal, and progenitor cells that are isolated from cultures of human heart biopsy[39,84]. They represent a niche-like environment, with cardiac-committed cells in the center and supporting cells in the periphery of the spherical cluster[85]. The cardiosphere-derived cells (CDCs) were originally isolated from mouse heart explants and human ventricular biopsies based on their ability to form three-dimensional (3D) spheroids in suspension cultures[86]. CDCs have grabbed much attention due to their proliferation and differentiation abilities by inherent stimulation of cardio-specific differentiation factors [GATA4, MEF2C, Nkx2.5, heart and neural crest derivatives expressed 2, and cardiac troponin T (TNNT2)] using a clustered regularly interspaced short palindromic repeat/dead Cas9 (CRISPR/dCas9) assisted transcriptional enhancement system[87,88]. Sano et al[89] have postulated that the CRISPR/dCas9 system may provide a proficient method of modifying TNNT2 gene activation in SCs. Consequently, CRISPR/dCas9 can improve the therapeutic outcomes of patients with ischemic heart disease by enhancing the transplanted CDCs differentiation capacity within the ischemic myocardium. Heart tissue is usually obtained by endomyocardial biopsy or during open cardiac surgery and grown in explants to form CDCs. CDCs have shown a superior myogenic differentiation potential, angiogenesis, and paracrine factor secretion as compared to other cell types. In heart failure animal models, the injected CDCs potentially differentiated into CMs and vascular cells. Additionally, CDCs have diminished unfavorable remodeling and infarct size, and hence improve cardiac function[90]. Accordingly, cardiospheres and CDCs may be some of the most promising sources of CPCs for cardiac repair.

The niche in the heart integrates several heterogeneous cell types, including CSCs, progenitors, fibroblasts, SMCs, CMs, capillaries, and supporting telocytes (TCs)[91], together with the junctions and cementing ECM that hold the niche together. Such architectural arrangement is essential for protection against external damaging stimuli and for preserving the stemness of the CSCs (Figure ). Without the niche microenvironment, CSCs lose their stemness and initiate differentiation eventually, leading to the exhaustion of the CSC pool. Similarly, in vitro studies require feeder layers and cytokines supplements in the culture media to ensure that SCs remain in their undifferentiated state[37].

Invivo arrangement of the central cardiac stem cells and the surrounding cells that comprise the niche (right side) and the in vitro derived cardio spheres (left side). The key delineates the types of cells identified in the niche and cardio spheres. Created with BioRender. CSC: Cardiac stem cell.

In vitro studies have recapitulated the niche theory using cardiospheres, which are 20150 m spheres (Figure ) of cells generated from the explant outgrowth of heart tissues[92,93]. Cardiospheres consist of CSCs in the core and cells committed to the cardiac lineage such as myofibroblasts, while vascular SMCs and ECs form the outer layer of the spheres. The 3D structure of cardiospheres protects the interiorly located CSCs from oxidative stress as well as maintain their stemness and function[84].

Accurate anatomical identification of CSCs in vivo remains a challenge due to the lack of basal-apical anatomical orientation as seen in epithelial organs such as the intestines[94]. Moreover, the heart does not comprise a specific compartment, where cells form a well-defined lining as seen in the bone marrow osteoblasts[95]. The adult heart epicardial lining anatomically contains several classes of niches, which are not limited to the sub epicardium[96] but dispersed throughout the myocardium, more in the atria and apex away from hemodynamic stress[97]. Some niches have been described in the atrio-ventricular junction of adult mouse and rat hearts[98] and interestingly in the human hearts[99]. The young mouse heart has been studied morphometrically to identify the location of CSCs niche and has been defined as a randomly positioned ellipsoid structure consisting of cellular and extracellular components. Within the niches, undifferentiated CSCs are usually assembled together with early committed cells that express c-KIT on surface, Nkx2.5 in the nucleus, and the contractile protein -sarcomeric actin in the cytoplasmic[97].

CSCs niche consists of clusters of c-kit+, MDR1+, and Sca-1+ cells[98] but lack the expression of the transcription factors and cytoplasmic or membrane proteins of cardiac cells[99,100]. Cardiac c-kit+/CD45- cells comprise about 1% of the CSC niche[97], are self-renewing clonogenic, and possess a cardiac multilineage differentiation potential comprise[101].

Within the niche, gap junctions (connexins) and (cadherins) connect SCs to their supporting cells, myocytes/fibroblasts. Conversely, ECs and SMCs do not act as supporting cells. Hence, the communication between CSCs with CMs and fibroblasts has been investigated by using in vitro assays[102]. The transmission of dyes via gap junctions between CSCs and CMs or fibroblasts was demonstrated previously and verified the functional coupling of these three cell populations[97]. In addition, micro ribonucleic acid (miRNA-499) translocates from CMs to CSCs comprising to the initiation of lineage specification and formation of myocytes[103].

Identification of SC niches is contingent upon the fulfillment of explicit criteria, including the recognition and determination of the affixing of SCs to their supporting cells as well as assuring the existence of an ancestor-progeny association[104]. Chemical and physical signals modulate the behavior of SCs within the niche. Amongst these signals are cytokines, cell surface adhesion molecules, shear forces, oxygen tension, innervation, and ions that serve as major determinants of SCs function[97]. Cell-to-cell signaling mediates the fate of SCs within the niches to promote self-renewal and favors their migration and differentiation. The fine-tuned crosstalk between SCs and their supporting cells regulates the state of the niche regarding quiescence or activity[105].

CSC niches, similar to the bone marrow, characteristically live in low oxygen tension, which favors a quiescent primitive state for SCs[106]. The longstanding perpetuation of the CSC niche requires a hypoxic environment, while physiological normoxia could be required for active cardiomyogenesis[107]. Hypoxic c-KIT+ CSCs within niches have been found throughout the myocardium, especially at the atria and apex. Throughout all ages, bundles of CSCs with low oxygen content coexist with normoxic CSCs niches. Hypoxic CSCs, especially in the atria, are quiescent cells undergoing cell cycle arrest and cannot divide. Normoxic CSCs are pushed into intense proliferation and differentiation with continuous telomere erosion, resulting finally in dysfunctional aged CMs[108]. Additionally, Nkx2.5 and GATA4 expressions are only restricted to the normoxic CSC niche. A balance between the hypoxic and normoxic niche is essential for the preservation of the CSC compartment and for the maintenance of myocardial homeostasis during the organ lifespan. Some factors such as aging cause an imbalance by expanding the hypoxic quiescent CSCs so that less pools of cycling CSCs maintain cell turnover[100]. Hypoxic cardiac niches are abundant in the epicardium and subepicardium in an adult mouse heart, which also fosters a metabolically distinctive population of glycolytic progenitor cells[109].

The pool of CSCs seems to be heterogeneous, incorporating quiescent and actively proliferating cells, migratory and adherent cells, uncommitted and early committed cells, with young and senescent cells. Additional surface epitopes remain to be disclosed to classify pools of CSCs holding specific properties. Surface Notch1 expression distinguishes multipotent CSCs that are poised for lineage commitment, while c-Met and ephrin type-A receptor 2 receptors reveal cells with particular migratory potential out of the niche area. A specific compartment of CSCs, expressing IGF-1 receptor, can be stimulated to regenerate damaged myocardium, while those expressing IGF-2 receptor hold higher probability for senescence and apoptosis. Although this arrangement of cells seems to equip properly the CSC with homeostasis regulation, it does not effectively protect against aging or ischemic injury of the heart[100].

Circulatory angiogenic cells (CACs) are endothelial progenitor cells involved in vasculogenesis, angiogenesis, and stimulating myocardial repair, mainly through paracrine action. Latham et al[110] demonstrated that conditioned medium from CACCSC co-cultures exhibited greatly mobilized CACs, with induction of tubule formation in human umbilical vein endothelial cells, mainly through the upregulation of the angiogenic factors angiogenin, stromal cell-derived factor 1 (SDF-1), and VEGF. Moreover, administration of CACs and CSCs in infarcted hearts of non-obese/severe combined immunodeficient mice restored substantially the left ventricular ejection fraction (LVEF), with reduction of scar formation as revealed by echocardiography. Successful yet modest SMCs, ECs, and CM differentiation has been also reported.

Pericytes (also called Rouget cells, mural cells, or perivascular mesenchymal precursor cells) are mesodermal cells that border the endothelial lining. They are highly proliferative cells and express neural/glial antigen 2, SOX-2, PDGFR-, CD34, and several mesenchymal markers such as CD105, CD90, and CD44. It was previously reported that the transplantation of saphenous vein-derived pericytes (SVPs) into an ischemic limb of an immunodeficient mice restored the local circulatory network via angiogenesis[111]. Moreover, treatment with SVP reduced fibrotic scar, CM death, and vascular permeability in a mouse model of MI via miRNA-132 facilitated angiogenesis[112]. Avolio et al[113] were the first to describe the relationship between SVP and the endogenous CSCs. Combined CSC and SVP transplantation in the infarcted myocardium of severe combined immunodeficient/Beige-immunodeficient mice showed similar results to treatment with CSCs or SVP cells per se, regarding scar size and ventricular function, indicating that SVPs alone are as potent as CSCs.

TCs represent a recently described cell population in the stromal spaces located in many organs, including the heart. They are broadly dispersed throughout the heart and comprise a network in the three cardiac layers, heart valves, and in CSC niches. TCs have been documented also in primary culture from heart tissues[114,115]. The ratio of cardiac TCs (0.5%-1%) exceeds that of CSCs. Although they still represent a minute portion of human cardiac interstitial cells, their extremely long and extensive telopodes allow them to occupy more surface area, forming a 3D platform probably that extends to support other cells[116]. The telopodes act as tracks for the sliding of precursor cells towards mature CMs and their integration into heart architecture[91]. TCs form a tandem with CSCs/CPCs in niches, where they communicate through direct physical contact by atypical junctions or indirect paracrine signaling[115].

TC-CSC co-culturing have suggested that TCs and CSCs act synergistically to control the level of secreted proteins, as shown by the increased levels of monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein1 and 2 (MIP-1 and MIP-2), and interleukin (IL)-13. Whereas, the level of IL-2 decreased compared to the monoculture of CSCs or TCs. IL-6 found in TC culture is behind the upregulation of these chemokines. Chemokines elucidated the role of TCs in directing the formation of CMs. Within the context, MIP-1 and MCP-1 play roles in the formation of SMCs in the airway. Additionally, MCP-1 is also involved in mouse skeletal muscle regeneration by recruiting macrophages. The enhancement of MCP-1 secretion serves as an activator of another cell population, primarily macrophages, which are generally involved in such processes[117].

IL-6 also activates downstream signaling pathways and contributes to cardioprotection and vessel formation in the heart through activation of gp130/signal transducer and activator of transcription 3. The Gp130/signal transducer and activator of transcription 3 is essential for the commitment of cardiac SCA-1+ cells into endothelial lineage[118].

Furthermore, IL-6 targets VEGF and hepatocyte growth factor (HGF) genes. VEGF has a mitogenic effect on CMs[119]. It is known to mobilize bone marrow-derived mesenchymal stem cells (BM-MSCs) into the peripheral blood in MI patients[120]. HGF and its receptor (c-Met) are also involved in cardiogenesis, as it is expressed early during cardiac development[121]. The level of HGF mRNA is normally low in the heart, but it is upregulated for at least 14 d after ischemic insult in rats, enhancing CMs survival under ischemic conditions[122,123]. Moreover, it has the potential to generate an adhesive micro-environment for SCs, as demonstrated in a study of transplantation of HGF transfected BM-MSCs in the infarcted myocardium[124]. HGF is also a powerful angiogenic agent, conducting its mitogenic and morphogenic effects through the expression of its specific receptor in various types of cells, including myocytes. Moreover, HGF exerts antifibrotic and antiapoptotic effects on the myocardium[125,126].

Transcriptomic analysis also has disclosed that TCs express pro-angiogenic miRNAs including let-7e, miRNA-21, miRNA-27b, miRNA-126, miRNA-130, miRNA-143, miRNA-503, and miRNA-100[127]. The TCs and CSCs interact in vitro forming atypical junctions, such as puncta adherentia and stromal synapses. The puncta adherentia consists of cadherincatenin clusters. It controls the symmetry of division by facilitating the proper positioning of centrosomes. Therefore, an increased number of CSCs has been reported to be encountered in the presence of cardiac TCs[128,129].

The paracrine potential of CSCs/CPCs has been recently under focus. CSC-derived cytokines and growth factors include epidermal growth factor (EGF), HGF, IGF-1, IGF-2, IL-6, IL-1, and TGF-1[130,131]. Exosomes appear to harbor relevant reparative signals, which mechanistically underlie the beneficial effects of CSCs transplantation[132].

Structurally, exosomes are lipid bilayer nano-sized organelles, 20-150 nm in diameter, secreted from all cell types, and function as intercellular communicators. Exosomes are highly heterogenic in content, and this stems from the unique packaging process that occurs inside progenitor and SCs. Exosomes carry lipids, proteins, and nucleic acids, with an abundance of miRNAs that hold profound post-transcriptional gene regulatory effects[133].

Amongst the distinctive protein content of cardiac exosomes are the chaperone proteins heat shock protein (HSP) 70 and HSP60. The HSP70 and HSP60, which under normal conditions assist in protein folding processes and deter misfolding and protein aggregation under pathological states induced by stress, also play major roles in apoptosis[134]. Circulating exosomes from healthy individuals have been found to activate cardioprotective pathways in CMs via HSP70 through extracellular signal-regulated kinase and HSP27 phosphorylation[135].

The exosome protein cargo of CPCs is distinct from BM-MSCs, fibroblasts, and other sources as it contains ample amounts of the pregnancy-associated plasma protein-A (PAPP-A). PAPP-A is present on the surface of human exosomes and interacts with IGF binding proteins (IGFBPs) to release IGF-1[136]. The cardioprotective role of CPCs-exosomes has been proven experimentally in in vitro ischemia/reperfusion and MI models and on CMs apoptosis to surpass that of BM-MSC-exosomes owing to their rich content of PAPP-A[137].

Like all exosomes, mouse CPCs-derived exosomes are positive for the surface markers CD63, CD81, and CD9, TSG-101, and Alix, however, they express a high-level of GATA4-responsive-miRNA-451. MiRNA-451 has been shown to inhibit CM apoptosis in an acute mouse myocardial ischemia-reperfusion model through inhibition of the caspases 3/7. The expression of miRNA-21 in the mouse CPCs-exosomes additionally justifies their CM protection against oxidative stress and antiapoptotic effects via inhibition of programmed cell death protein 4 (PDCD4)[138]. Human CPCs-exosomes are enriched with miRNA-210, miRNA-132, and miRNA-146a-3p, which account for the diminished CM apoptosis, enhanced angiogenesis, and improved LVEF[139]. MiRNA-146a-5p is the most highly upregulated miRNA in human CPCs-exosomes and targets genes involved in inflammatory and cell death pathways[137].

The CDCs contain CD34+ stromal cells of cardiac origin and are multipotent and clonogenic but not self-renewing[140]. CDCs secrete exosomes that induce cardiomyogenesis and angiogenesis, regulate the immune response, downgrade fibrosis, and improve the overall cardiac function[141,142]. Moreover, CDCs homogeneously express CD105 but not CD45 or other hematopoietic markers. They also exhibit a high expression of miRNA-126[143]. Circulating miRNA-126 may participate in cardiac repair during acute MI and has been demonstrated to be downregulated in heart damage[144].

While exosomes are constitutively secreted, changes in the surrounding microenvironment, such as hypoxia, can induce modifications in CPCs- and CM- derived extracellular vesicles. Hypoxic CMs secrete large extracellular vesicles containing long noncoding RNA neat 1 (LNCRNA NEAT1), which is transcriptionally regulated under basal conditions by p53, while during hypoxia it is regulated by the hypoxia inducible factor 2A. An uptake of the hypoxic CM-derived extracellular vesicles by fibroblasts can prompt the expression of profibrotic genes[145]. Oxidative stress may also induce the release of cardiac CPCs exosomes, which in turn inhibit apoptosis when taken up by H9C2 (rat cardiomyoblast cell line)[132]. Furthermore, oxidative stress stimulates secretion of miRNA-21 rich exosomes, which could inhibit H9C2 apoptosis by targeting PDCD4 and hence can be accounted as a new method to treat ischemia-reperfusion[138].

Intercellular communication via exosomes occurs as part of various biological processes, including immune modulation, vasculogenesis, transport of genetic materials, and pathological conditions such as inflammation, apoptosis, and fibrosis, which can lead to cardiovascular disease when altered[146]. Hence, isolation and analysis of cardiac exosomes contents, mainly miRNA and proteins, could offer diagnostic information for several cardiovascular diseases[147] (Figure ).

Schematic diagram elucidating the diverse exosomal contents that serve as biomarkers for several cardiovascular diseases. Created with BioRender.com. HSP: Heat shock protein; lncRNA: Long non-coding RNA; miR: MicroRNA.

Functionally, exosomes mediate several intra-cardiac inter-cellular communications such as:

CPC-CM crosstalk through factors, such as miRNA-146a and PAPP-A, which activate extracellular signal-regulated kinases 1/2 pathway and inhibit apoptosis[139].

CPC-macrophage (M1) crosstalk via miRNA-181b and Y-RNA fragment transforms M1 to M2 macrophages with attenuated proinflammatory cytokines and increased IL-10[148,149] (Figure ).

Possible cardiac reparative effects of cardiac stem cell/cardiosphere-derived cell-derived exosomes in myocardial ischemia and ischemia/reperfusion injury. Created with BioRender.com. CSC: Cardiac stem cell; IL: Interleukin; IR: Ischemia/reperfusion; miRNA: MicroRNA; PI3K: Phosphoinositide 3-kinase; SDF-1: Stromal cell-derived factor 1; VEGF: Vascular endothelial growth factor.

CPC-fibroblast interaction via exosomes primes the fibroblasts and increases expression of VEGF and SDF-1. Experimental injection of fibroblasts primed with CPCs-exosomes into the myocardium of a MI model proved to reduce infarct size and improve cardiac function. In addition, cardiosphere-isolated exosomes have been used to prime inert fibroblasts, leading to an intensification of their angiogenic, cardiomyogenic, antifibrotic, and collective regenerative effects[150] (Figure ).

CPC-self regulatory mechanisms: Exosomes derived from CPCs may play critical roles in maintaining the self-renewal state of CPCs themselves and balance their differentiation, i.e. preserve their stemness[151] (Figure ). The CPC-derived exosomes activate the endogenous CPCs by transferring signal molecules directly within their niche[152].

CPC-derived exosomes release various RNA species in the extracellular space, modulating endogenous SC plasticity and tissue regeneration through their cytoprotective, immunomodulatory, pro-angiogenic, and anti-apoptotic actions[153].

Fibroblasts and pericytes interact after transdifferentiating to myofibroblasts and deposit ECM causing cardiac fibrosis. These fibrotic changes are usually induced by cardiac damage and lead to scar formation. Exosomes serve as messengers for cell-to-cell communication during cardiac fibrosis[154]. Molecular mechanisms of cardiac fibrosis are primarily related to TGF- pathways, IL-11 signaling pathway, nuclear factor- pathway, and Wnt pathways[155]. Accordingly, the bioactive substances targeted at these pathways could hypothetically be applied in the treatment of cardiac fibrosis. Wnt3a, being highly expressed in exosomes, could activate the Wnt/-catenin pathway in cardiac fibroblasts by restricting GSK3 activation[156]. Moreover, tumor necrosis factor contained in exosomes can be transferred between cardiac myocytes. In general activation/inhibition of the exosomes conveying remodeling substance secretion or uptake can control the myocardial remodeling and repair following MI[154,157].

The highlighted complex cell-to-cell communication from endogenous or exogenous CSCs provides an optimal microenvironment for resident CPC proliferation and differentiation (Figure ), rendering the environment receptive to transplanted CPCs. This adaptation is promoted through activation of pro-survival kinases, leading to the induction of a glycolytic switch in recipient CPCs[158].

Data from experimental models suggest that the exosomal component of the CPC secretome can fully recapitulate the effects of cellular therapy on ischemic and non-ischemic heart models[140]. In an ischemia-reperfusion injury rat model, Ciullo and partners[159] have shown that the systemic injection of exosomes (genetically manipulated to overexpress CXCR4ExoCXCR4) improve cardiac function. Additionally, expression of hypoxia-inducible factor 1 (HIF-1) in the infarcted myocardium is upregulated through the stimulation of SDF-1. The latter is one of the CXC chemokine family overexpressed in heart post-MI that readily attaches to the CXCR4 receptor and acts as a potent chemoattractant for CXCR4 expressing circulating progenitor cells. The ExoCXCR4 are more bioactive in the infarcted zone than naturally occurring exosomes injected via tail-vein, confirming their superior homing and cardioprotective properties in the damaged heart.

Gallet et al[160] postulated the safety and efficiency of CDC-derived exosomes in acute and chronic myocardial injury animal models. Within the context of experimental research to validate the paracrine hypothesis for CDCsderived exosomes, it has been proven that human CDC-exosomes can recapitulate CDC therapy and boost cardiac function post-MI in pig models. Intramyocardial injection of human CDC-exosomes has resulted in higher exosome retention and efficacy as compared to intracoronary injection, with great reduction of scar size and increased ejection fraction. This indicates that the route of administration is imperative for full functional capacity of the exosomes. Subsequently, the researchers have devised a randomized preclinical study by means of a NOGA-guided intramyocardial exosome injection. Decreased collagen content in the infarct and border zone and increased neovascularization and Ki67+ CMs are indicative of the reparative functions of CDC-exosomes. Notably, human CDC-exosomes have shown a lack of an immune reaction, as seen by the lack of inflammatory reactions or CM necrosis in pig models. These observations strongly support the view that CDC-exosomes are ready to be tested in clinical trials.

Similar promising outcomes were observed in a Duchenne muscular dystrophy model (mdx), in which intramyocardial injection of CDC-exosomes efficiently recapitulated the effects of CDC injection on cardiac function, leading to recovery of movement. Administration of CPC-derived exosomes has resulted in transient restoration of partial expression of full-length dystrophin in mdx mice[161]. Further studies assessed the therapeutic potential of CPC-exosomes in a doxorubicin cardiotoxicity model and non-ischemic heart disease[162]. In addition, two concluded phase I clinical trials in patients with heart failure and revealed the capacity of CDCs to enhance cardiac function by reducing ventricular remodeling and scar formation. Despite receiving a single injection at the beginning of the study, the improvement in cardiac function was noted after the 1-year follow-up. This finding consequently leads to the proposition that transplanted CDCs mainly have imposed their actions at the site of injury by secreting paracrine factors including exosomes. In other words, CDC-exosomes achieved a biphasic beneficiary regenerative effect involving acute cardio protection coupled with long-term stimulation of endogenous cardiac repair[163].

While the fetal heart obtains most of its ATP supply via glycolysis[164], the adult heart relies mainly on fatty acid oxidation to fulfill the contracting myocardium high energy demand[164,165]. The loss of the regenerative phenotype is related to the oxidative metabolism of glucose and fatty acids[166,167] and is mediated by various physiological changes including increased workload and the demand for growth, which cannot be solely met by glycolysis[168,169], as well as postnatal increase in both circulating levels of free fatty acids and blood oxygen levels[164,165]. Studies have shown the involvement of the HIF-1 signaling pathway[170], peroxisome proliferator-activated receptor (PPAR)[171], and peroxisome proliferator-activated receptor coactivator-1 (PGC-1) in the switch toward oxidative metabolism[172], which is accompanied by dramatic increase in the number of mitochondria in CMs[173].

Notably, similar metabolic reprogramming occurs during differentiation from cardiac SCs to CMs[167]. Studies reported that after differentiation into CMs, there is an increase in the mitochondrial number and activity[174], increased oxidative metabolism[175], and increased respiratory capacity resulting in an increased adenosine diphosphate:ATP ratio[173] after differentiation into CMs.

The fact of the various metabolic changes that accompany the transition from glycolysis to fatty acids oxidation affect cardiac cell maturation[164,167] has mandated the consideration of substrate composition in cardiac differentiation protocols[167].

A study by Malandraki-Miller et al[176] investigated the effect of fatty acid supplementation, which mimics the metabolic switch from glucose to fatty acid oxidation, on adult cardiac progenitors. The study used radiolabeled substrate consumption for metabolic flux to investigate the role of the PPAR/PGC-1 axis during metabolic maturation. Oleic acid stimulated the PPAR pathway, enhanced the maturation of the cardiac progenitor, and increased the expression of MHC and connexin after differentiation. Moreover, total glycolytic metabolism, mitochondrial membrane potential, the expression of glucose, and fatty acid transporter increased. The recorded results contributed greatly in highlighting the role of fatty acids and PPAR in CPC differentiation.

Another study by Correia et al[177] has linked substrate utilization and functional maturation of CMs via studying the effect of the metabolic shift from glucose to galactose and fatty acid-containing medium in the maturation of hPSCs-derived CMs (hPSCs-CMs). The shift accelerated hPSC-CM maturation into adult-like CMs with higher oxidative metabolism, mature transcriptional signatures, higher myofibril density, improved calcium influx, and enhanced contractility. Galactose improved total oxidative capacity with reduction of fatty acid oxidation, thereby protecting the cells from lipotoxicity.

In CDCs, oxidative metabolism and cell differentiation reciprocally affect each other. In vitro cultures for CDCs revealed a PPAR agonist that triggers fatty acid oxidation. Metabolic changes have been characterized as the CDC differentiated towards a cardiac phenotype. Addition of a PPAR agonist at the onset of differentiation has induced a switch towards oxidative metabolism, as shown by changes in gene expression with decreasing glycolytic flux and increasing oxidation of glucose and palmitate. Undifferentiated CDCs have generated high levels of ATP from glycolysis and from oxidation of acetoacetate. Upon differentiation, oxidative metabolism of glucose and fatty acids is upregulated with decreased oxidation of acetoacetate, a metabolic phenotype similar to that of the adult heart[178].

Taken together, the metabolic hallmarks of differentiated CMs vary from their undifferentiated SCs. Energy substrate metabolism during cardiac development and differentiation shows gradual decrease in the contribution of glycolysis to ATP synthesis with simultaneous increase in fatty aciddependent mitochondrial respiration[179].

Common methods for the investigation of substrate metabolism include the measurement of metabolic fluxes using radio-labeled substrates, such as D-U-14C-glucose[180,181] as well as measurement of mitochondrial oxygen consumption rate and extracellular acidification rate using the XF Extracellular Flux Analyzer (Seahorse Bioscience, North Billerica, MA, United States)[182,183].

Recently, a detailed protocol for metabolic characterization of hiPSCs-CMs has been developed. The hiPSCs are obtained from adult somatic cells via novel cell reprogramming approaches, followed by differentiation to CMs. The novel in vitro cardiac cellular model provided new insights into studying cardiac disease mechanisms and therapeutic potentials. The characterization protocol measures small metabolites and combines gas- and liquid-chromatography-mass spectrometry metabolic profiling, lactate/pyruvate, and glucose uptake assays as important tools[184]. Integration between the implemented assays has provided complementary metabolic characteristics besides the already established electrophysiological and imaging techniques, such as monitoring ion channel activities[185], measurement of action potentials, changes in Ca+2 fluxes[186], and mitochondria viability and apoptosis[187].

An alternative pathway for glucose metabolism in CMs involves the entry of glucose-6-phosphate (G6P) in the pentose phosphate pathway, with resultant generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH)[188]. Reduced NADPH helps to regenerate reduced glutathione and thus acts protectively against reactive oxygen species induced cell injury.

The cardioprotective role of the pentose/G6P/NADPH/glutathione pathway has been emphasized by Jain et al[189] who demonstrated that G6P dehydrogenase (G6PD) lacking mice have more severe heart damage induced by the myocardial ischemia reperfusion injury in Langendorff-perfused hearts as compared with wild-type mice.

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Cardiac stem cells: Current knowledge and future prospects

Cardiac Stem Cells Comments Off on Cardiac stem cells: Current knowledge and future prospects | April 13th, 2023

Cardiovascular diseases represent the world's leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.

Keywords: Cardiac stem cell; Cardiovascular diseases; Cell therapy; Pluripotent stem cells; Progenitor cardiac cells; Stem cell.

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Stem cell therapies in cardiac diseases: Current status and future ...

Cardiac Stem Cells Comments Off on Stem cell therapies in cardiac diseases: Current status and future … | April 13th, 2023

Reparative stem cells have the capability to restore function to damaged tissue by renewing cell growth (shown in green) in cardiac cells destroyed by heart disease.

Approximately 28 million Americans have been diagnosed with heart disease. Traditional medical therapies are not able to fully address the burden of disease, and the shortage of organs for transplantation remains a key barrier more than 117,000 people are on the national transplant list.

This unmet need drives Mayo Clinic researchers to make new discoveries to accelerate regenerative solutions into clinical trials and rapidly provide new hope to patients who can't currently be treated.

Cardiac regeneration is a broad effort that aims to repair irreversibly damaged heart tissue with cutting-edge science, including stem cell and cell-free therapy. Reparative tools have been engineered to restore damaged heart tissue and function using the body's natural ability to regenerate. Working together, patients and providers are finding regenerative solutions that restore, renew and recycle patients' own reparative capacity. Through the vision and generous support of Russ and Kathy Van Cleve, strong efforts are underway to develop discoveries that will have a global impact on ischemic heart disease.

Mayo Clinic researchers are leading efforts in translating new knowledge into applicable therapeutics through a multidisciplinary community of practice. As technology evolves, it offers the potential to regenerate cardiac tissue from noncardiac sources and ultimately provide personalized products and services to people with cardiovascular disease.

The overarching vision for the cardiac regeneration program at Mayo Clinic is to develop new therapies to cure ischemic heart disease. Mayo researchers are developing products for clinical testing that span the disease spectrum, including the following areas:

More information about cardiac regenerative medicine research at Mayo Clinic is on the Van Cleve Cardiac Regenerative Medicine Program website.

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Center for Regenerative Biotherapeutics - Cardiac Regeneration

Cardiac Stem Cells Comments Off on Center for Regenerative Biotherapeutics – Cardiac Regeneration | April 13th, 2023

The limited regenerative capacity of the heart is a major factor in heart failure and death. Once cardiac cells are diseased, its hard for them to heal like your body would with a cut. Studying how the heart forms in fetuses and then matures is a natural step for researchers interested in generating and regenerating heart cells. Theyre also investigating the effect of stem cell-derived cardiac cells on repairing damaged hearts and their potential to treat heart muscle diseases.

Cardiovascular progenitor cells (CPCs), a type of heart cell, are called building blocks because theyre used to form the heart during fetal development. They hold tremendous therapeutic potential because of their unique ability to develop into several different heart cell types. Researchers are studying how CPC cells can renew themselves in mice. Theyre studying whether this renewal also occurs in humans and whether this is useful for repairing damaged hearts.

Because CPCs regenerate, scientists may be able to grow them in a dish. Its not as easy to grow cells in a lab as it is in the body they often have developmental arrest and dont mature. However, a recent discovery of the pathways that lead a fetal cell into an adult cell will enable researchers to recreate adult heart tissue in the lab, which holds tremendous potential for new heart disease treatment.

Videos Heart tissue grown in a dish

Heart tissue grown in a dish from mouse cardiac progenitor cells (CPCs). The CPCs, and the tissue they built, were engineered to produce a red protein.

View labs and centersAdult Cardiac Catheterization LabCiccarone CenterChulan Kwon LabHeart and Vascular InstituteCardiovascular Stem Cell Program

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Stem Cell and Regenerative Biology | Johns Hopkins Heart and Vascular ...

Cardiac Stem Cells Comments Off on Stem Cell and Regenerative Biology | Johns Hopkins Heart and Vascular … | April 13th, 2023

Anika Continues to Expand Addressable Market for Tactoset Injectable Bone Substitute with Additional 510(k) Clearance from FDA  Marketscreener.com

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MorphoSys Completes Enrollment of Phase 3 MANIFEST-2 Study of Pelabresib in Myelofibrosis with Topline Results Expected by End of 2023  Marketscreener.com

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INTERNATIONAL STEM CELL CORP MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K)  Marketscreener.com

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VOR BIOPHARMA INC. Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-K)  Marketscreener.com

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VOR BIOPHARMA INC. Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-K) - Marketscreener.com

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MAGENTA THERAPEUTICS, INC. MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K)  Marketscreener.com

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MAGENTA THERAPEUTICS, INC. MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K) - Marketscreener.com

Cardiac Stem Cells Comments Off on MAGENTA THERAPEUTICS, INC. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K) – Marketscreener.com | March 25th, 2023

BioRestorative Therapies to Seek FDA Approval to Expand the Clinical Application of BRTX-100  Marketscreener.com

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BioRestorative Therapies to Seek FDA Approval to Expand the Clinical Application of BRTX-100 - Marketscreener.com

Bone Marrow Stem Cells Comments Off on BioRestorative Therapies to Seek FDA Approval to Expand the Clinical Application of BRTX-100 – Marketscreener.com | March 17th, 2023

BioSenic delivers a new post-hoc analysis of its Phase III JTA-004 trial on knee osteo-arthritis with positive action on the most severely affected patient population  Marketscreener.com

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BioSenic delivers a new post-hoc analysis of its Phase III JTA-004 trial on knee osteo-arthritis with positive action on the most severely affected...

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Regenerative Therapies Market is Set to Grow at a CAGR of 8.7% by 2033, Propelled by Advancements in  EIN News

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JASPER THERAPEUTICS, INC. MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K)  Marketscreener.com

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For a range of unmet medical needs, India offers a fantastic opportunity to push cell and gene therapies: B ..  ETHealthWorld

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The body is always in a state of change. In particular, the cells in your skin are constantly replacing themselves.

The skin does this through the process of regeneration and repair.

On a cellular level, the skin cells are constantly shedding, revealing fresh, newly grown skin cells underneath. This is why scars and blemishes may fade a bit with time.

Understanding the science behind your skins life cycle can help you to take care of your skin as it goes through the regeneration process. It can also help you boost your skins natural regeneration process and give you a fresh glow.

Heres what the skin care experts have to say about how to speed up skin regeneration.

According to 2015 research, skin regeneration refers to the complete replacement of damaged tissue with new tissue. Skin repair refers to the continued healing process of existing tissue. Skin regeneration isnt usually associated with scar tissue.

The research goes on to say that skin regeneration can happen in two ways:

Skin regeneration is a natural physical process that occurs on a cellular level.

The epidermis cells, or top layers of skin, continuously replace themselves, explains Laura Chacon-Garbato, a licensed esthetician and director of education at Herbalife. This process of renewal is the process of shedding the epidermis.

In other words, skin regeneration is a constant renewal of cells.

According to a 2010 review, the epidermis is maintained by stem cells in the lowest layer of the skin. These epidermal stem cells generate daughter cells that move upward toward the surface of the skin.

During this journey, cells that produce keratin undergo a series of biochemical and morphological changes that result in the formation of the various layers of the skin.

This gives skin a young, healthy glow, adds Jennifer Hurtikant, chief science officer at Prime Matter Labs.

The same study mentioned above estimated that the epidermis turns over every 40 to 56 days on average.

When were young, the process of exfoliation happens naturally, but as we age this process is altered and slows down, Chacon-Garbato says.

An older 2006 study notes that the usual 28-day turnover time for skin increases approximately 30 percent to 50 percent by age 80.

For people over 50 years old, Chacon-Garbato says, the process can take as long as 84 days.

The effects of the slowdown cause buildup and an excess of dead skin cells that can make the skin look tired, dull, and opaque, she says.

Throughout this process, several things occur on a cellular level.

First, new skin cells are formed deep in the epidermis.

Then, as the skin cells mature and die on the upper layer of the epidermis, they naturally fall away.

If you have a cut or burn, you may be left with a scar.

This is because fibroblasts in scar tissue form collagen differently than in regular tissue. As a result, its thicker and less flexible than regular skin tissue.

However, by improving skin regeneration, you may notice that scars gradually fade away as fresh, healthy skin tissue forms beneath them.

As you get older, skin regeneration slows down. This leaves an accumulation of dead skin cells on the upper layer of the skin.

By boosting the natural regeneration process, you can help the skin look fresh and feel elastic, even as you age.

Making healthy choices can help to keep the skin regeneration process functioning optimally.

Hurtikant suggests:

There are two types of aging, cellular or intrinsic aging and environmental or extrinsic aging.

Intrinsic aging is a genetically predetermined process that occurs naturally, but may increase with stress. Extrinsic aging is a result of outside factors, like where you live and your lifestyle habits.

Stress causes intrinsic aging and the environment causes extrinsic aging, Hurtikant says.

Chacon-Garbato recommends eating plenty of protein, such as:

Proteins are essential for tissue repair and the construction of new tissue, she says. Cells need protein to maintain their life, so the body uses protein to replace worn-out or dead skin cells.

In addition, favor foods that are high in antioxidants, like:

Including antioxidants in your diet may help improve the glow and luster of the skin.

Specific skin care products can also help improve the natural cell turnover process, hydrate the skin, and get rid of built-up dead skin cells. Look for ingredients like:

Use products with vitamin B3, Chacon-Garbato suggests. Its a necessary component of cell metabolism, also known as niacinamide, and is required for many skin processes that help maintain healthy-looking skin.

She also suggests using antioxidants such as vitamin C and E to prevent cellular damage from free radicals.

Try Swisse Beauty Skin Regeneration+, an oral supplement with ALA, and Musely FaceRx Anti-Aging Night Cream with tretinoin, hyaluronic acid, and niacinamide.

These natural remedies may help boost your skins health and promote the skin regeneration process:

A 2022 study found that several plant extracts, including papaya, showed antioxidant, and antiwrinkle effects. Extracts that used ethanol as a cosolvent showed greater effects.

A 2018 review found that jojoba, rosehip, and coconut oil may help with skin barrier repair, wound healing, antioxidant effects, and antiaging.

A 2010 study noted that orange peel extract could provide useful protection against or alleviation of UV damage.

You can look for natural skin care products that contain these ingredients.

Citrus can increase photosensitivity, or sensitivity to light. Use caution when applying citrus in any form to the skin by avoiding direct sun exposure and using sun protection. Never apply citrus oils directly to the skin.

If you want to exfoliate a little deeper, a dermatologist may be able to offer a more intensive skin resurfacing procedure to kick-start skin rejuvenation. Make sure you find a dermatologist who is board certified.

Chacon-Garbato suggests:

However, she notes, theres no one-size-fits-all for the skin, so its important to check with your dermatologist to help define the best approach for the results you want to achieve.

Want to know more? Get the FAQs below.

Aloe vera encourages cell diversity and helps keep the skin well hydrated and protected.

According to a 2020 study, it also boasts natural antioxidant and anti-inflammatory properties.

Aloe vera is an excellent ingredient to use daily because its well known for its revitalizing and calming properties, Chacon-Garbato says. Its also a hugely effective hydrator and helps to minimize skin dryness.

She notes that its been used for centuries for beauty because of its many benefits, including delivering moisture directly to the tissue and helping prevent water loss due to evaporation.

Hurtikant adds that while aloe vera is great for boosting regeneration, there are other ingredients to try too.

Trending ingredients for skin regeneration are derivatives of algae and mushrooms, and hyaluronic acid, she says.

There are plenty of skin care products that have been shown to improve the appearance of aging in the skin by speeding up the natural skin regeneration process.

One highly rated product is Musely FaceRx Anti-Aging Night Cream, which includes active ingredients such as tretinoin (Retin-A), niacinamide, and hyaluronic acid.

These three ingredients are all excellent for encouraging exfoliation. Keep an eye out for them on the ingredients list when youre looking for good creams to promote regeneration.

For most adults under 50 years old, the cycle lasts between 28 and 42 days. For adults over 50 years old, this may increase to up to 84 days, though the number varies.

The time it takes for your skin to complete the skin regeneration cycle depends on a range of factors, including:

There are a range of ways to improve skin regeneration.

Simple lifestyle changes like exercise and increased hydration can keep the process working properly.

Skin creams that include exfoliating ingredients can also help to get rid of excess dead skin.

Some procedures can also encourage faster growth of new skin cells to speed up the regeneration process.

Aging slows down the skin regeneration process, but it doesnt ever stop it completely.

However, because the process becomes much slower as we age, the skin can appear thicker, less flexible, and more wrinkled or textured.

This is because the slower the regeneration, the more dead skin cells remain on the face.

Skin regeneration is a natural cycle that occurs as the skin cells turn over. In other words, dead skin cells on the top layer of the epidermis fall away, revealing fresh, newly created cells beneath.

By supporting this cycle with a healthy lifestyle and skin care routine, you can encourage a lustrous glow even as you get older.

Just remember: while boosting skin regeneration is possible, its natural for the cycle to slow down as you age. A few wrinkles and some texture are nothing to be ashamed of.

You can even think of them as signs of wisdom and experience.

Meg is a freelance journalist and features writer who covers culture, entertainment, lifestyle and health. Her writing has appeared in Cosmopolitan, Shondaland, Healthline, HelloGiggles, Readers Digest, Apartment Therapy, and more. T: @wordsbyMeg W: megwalters.co.uk

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Skin Regeneration: The Science and How to Boost It - Healthline

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