EditorialStem/Progenitor Cells in Cardiopulmonary Health, Disease,and Treatment

Fatemeh Sharifpanah ,1 Hossein A. Ghofrani,2,3 Suk Ying Tsang,4,5,6,7

and Heinrich Sauer 1

1Department of Physiology, Faculty of Medicine, Justus Liebig University, Giessen, Germany2Department of Internal Medicine, Justus Liebig University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC),German Center for Lung Research (DZL), Giessen, Germany3Department of Medicine, Imperial College London, London, UK4School of Life Sciences, The Chinese University of Hong Kong, Hong Kong5Key Laboratory for Regenerative Medicine, Ministry of Education, The Chinese University of Hong Kong, Hong Kong6State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong7Centre for Novel Biomaterials, The Chinese University of Hong Kong, Hong Kong

Correspondence should be addressed to Fatemeh Sharifpanah; fatemeh.sharifpanah@med.uni-giessen.de

Received 23 October 2018; Accepted 23 October 2018; Published 6 January 2019

Copyright © 2019 Fatemeh Sharifpanah et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work is properly cited.

The cardiopulmonary system comprises various organs,structures, and substances from both the heart and lungsystems. Since the cardiopulmonary system interacts inti-mately with every other system in the body and our healthis closely related to the function of the cardiopulmonarysystem, its function and maintenance were always the centerof attention by scientists and clinicians. Despite plentifulresearch in this area, cardiopulmonary diseases still remainwidely prevalent and are known as a significant and devas-tating cause of morbidity and mortality on the globe. Themost common cardiopulmonary diseases are hypertension,chronic obstructive pulmonary disease, coronary heart dis-ease, and rheumatic heart fever. Generally, cardiopulmonarydisorders have a poor prognosis and current treatments onlyoffer a modest improvement of symptoms without repairingthe damaged tissues in the heart or lung system. But recentprogress in the field of stem cell science, regenerative medi-cine, and tissue engineering offered a new perspective in thetreatment of cardiopulmonary disorders.

This great achievement provided tremendous potential todevelop disease- and patient-specific induced pluripotentstem (iPS) cells as well as organoid cultures for gatheringdetailed insight into the pathomechanisms of various cardio-pulmonary disorders which is important in drug discovery

and treatment of patients. Furthermore, the revolutionizedprogress in the stem cell field has opened a great opportunityfor novel personalized regenerative therapeutic approachesto treat cardiopulmonary disorders. There is abundant andeven growing number of evidence in stem/progenitor celltherapy of various cardiopulmonary disorders of which somegenerated controversial information. To summarize andincorporate these scattered data and develop a more compre-hensive understanding on the impact of stem/progenitorcells in the cardiopulmonary system, the Stem Cells Interna-tional journal sets out to publish a special issue focused on“Stem/Progenitor Cells in Cardiopulmonary Health, Disease,and Treatment” which covers research from diverse disci-plines related to cardiopulmonary health. This special issuesums up recent findings concerning the essential role ofstem/progenitor cells in the cardiac as well as pulmonarysystem. It includes selected reviews and original articlesdiscussing the role and properties of stem/progenitor cellsnot only from the perspective of basic science but also fromthe perspective of therapeutic strategies.

As known, the human adult heart lacks a robust endoge-nous repair mechanism and is not able to regenerate andrepair itself after injuries. Therefore, developing and estab-lishing approaches to regenerate and repair the injured heart

HindawiStem Cells InternationalVolume 2019, Article ID 9861403, 4 pageshttps://doi.org/10.1155/2019/9861403

are a top priority in treating heart failure. One of the mostpromising therapeutic strategies for cardiac injury treatmentis cell therapy. But before using cell therapy for treatingpatients, it is necessary to be able to efficiently generate asufficient number of functional cardiomyocytes which arecapable to functionally and safely integrate into the injuredarea of the heart. The recently developed “direct cardiacreprogramming” technique is a promising approach forgenerating functional cardiomyocytes. J. L. Engel and R.Ardehali on their review article entitled “Direct CardiacReprogramming: Progress and Promise” have comprehen-sively reviewed the key transcription factors and cardiogenicgenes as well as various biological molecules (e.g., epigeneticmodifiers, noncoding RNAs, and small molecules) whichimprove the efficiency of cardiac reprogramming to developsafer reprogramming approaches for future clinical applica-tions. In this context, Y. Zhou et al. have examined the func-tion of various epigenetic factors involved in chromatinremodeling and RNA splicing to identify the inhibitory orfacilitating effects of these factors in direct cardiac repro-gramming. As they have reported on their interestingresearch article entitled “A Loss of Function Screen of Epige-netic Modifiers and Splicing Factors during Early Stage ofCardiac Reprogramming,” the splicing factors Sf3a1 andSf3b1 are essential regulators for direct reprogramming,while the splicing factor Zrsr2 as well as the epigenetic mod-ulators Bcor and Stag2 functions as inhibitory barriers fordirect cardiac reprogramming. They have finally highlightedthe impact of epigenetic regulation and the RNA splicingprocess during cell fate conversion. As it is also discussedby J. L. Engel and R. Ardehali, small molecules can be usedto improve the efficiency of cardiac regeneration. Varioussmall molecules are intensively investigated by differentgroups for more profound understanding of the cardiacregeneration process which can be potentially used for thedevelopment of new therapeutic strategies for heart failuretreatment. In this regard, E. H. Ali et al. have investigatedthe translational potential of the small molecule silibinin incardiomyogenesis of embryonic stem cells. The small mole-cule silibinin is a natural compound isolated frommilk thistleseed extracts and is traditionally used as a hepatoprotectant.In research article “The Milk Thistle (Silybum marianum)Compound Silibinin Inhibits Cardiomyogenesis of Embry-onic Stem Cells by Interfering with Angiotensin II Signaling”authored by E. H. Ali et al., it has been demonstrated thatsmall molecule silibinin as an inhibitor of the angiotensin IItype 1 (AT1) receptor inhibits the cardiomyogenesis processof embryonic stem cells by interfering with angiotensin IIsignaling downstream of the AT1 receptor.

Amongst multiple therapeutic approaches and variouspharmacological agents which have shown an improvementin patient care and decrease ofmortality rate, stem/progenitorcell-based therapeutic approaches present the most promis-ing approach to treat the cardiopulmonary disorders in thefuture. S. Bardelli and M. Moccetti on their article entitled“Stem and Progenitor Cells in Human CardiopulmonaryDevelopment and Regeneration” have briefly reviewed thecontribution of stem/progenitor cells in the development ofthe cardiopulmonary system as well as the cellular plasticity

potential of stem/progenitor cells in the regeneration of theinjured heart and lung organs and their current therapeuticapplications in the treatment of cardiopulmonary diseases.In this regard, N. Witman and M. Sahara in the review articleentitled “Cardiac Progenitor Cells in Basic Biology andRegenerative Medicine” have comprehensively discussedthe biology of embryonic and adult cardiac progenitor cellsand their regenerative capabilities as well as their currentclinical applications in cardiac repair. Cardiac progenitorcells are a heterogeneous cell population distributed through-out the heart which are quiescent under physiological condi-tions and become activated after injury and may differentiateinto new myocytes and vascular cells [1]. J. L. Engel andR. Ardehali review a novel technique which is generatingexpandable cardiac progenitor cells by direct reprogrammingin culture for transplantation in their abovementionedreview article.

Mesenchymal stem cells (MSCs), the major stem cells forregenerative cell-based therapy, have been characterized byDr. Alexander Friedenstein over 40 years ago and are widelyused for treating a variety of diseases. Along with the immu-nomodulatory and differentiation potential of MSCs, it hasbeen shown that they express various essential cytokineswhich stimulate local tissue repair [2]. The review made byJ. Gronbach et al. entitled “The Potentials and Caveats ofMesenchymal Stromal Cell-Based Therapies in the PretermInfant” has essentially described the role of stem cells in lungdevelopment as well as pulmonary diseases. They have fur-ther discussed the potential and challenges of mesenchymalstem cell-based therapies in preterm infants and explainedthe positive effects of exogenous MSC therapy in the diseasedlung with the special focus on the bronchopulmonary dyspla-sia, a chronic lung disease of preterm infants. AlthoughMSC-based therapies are a highly promising approach fortreating patients, the authors explained that still a lot ofresearch is needed to bring optimized MSC products intoupcoming clinical trials and their outcomes have to be criti-cally evaluated before a broad introduction of MSC-basedtherapies into the clinics can be achieved. One of the mostimportant points for optimizing MSC products is mainte-nance and expansion of MSCs in culture before transplanta-tion. With a well optimized protocol, it will be possible togenerate a sufficient cell number with the best quality neededfor transplantation. Despite regulatory issues about usinganimal-derived cell culture supplements in clinic, most clin-ical trials of MSC-based cell therapies are still dependent onfetal bovine serum for cell expansion before transplantation.In order to solve this problem, T. Z. Nazari-Shafti et al. haveinvestigated the effect of human serum from heart failurepatients and also healthy donors on cord blood MSCs duringregular short-term cultivation as well as stimulated acuteand chronic stress conditions and compared their resultswith the findings from cells treated with fetal bovine serumin the same conditions on their research article entitled“Mesenchymal Stromal Cells Cultured in Serum from HeartFailure Patients Are More Resistant to Simulated Chronicand Acute Stress.” They have demonstrated that autologoushuman serum will be a valid alternative to fetal bovine serumin cell-based therapies addressing severe heart disease.

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Cell-based therapies using MSCs are widely used fortreating various pathological conditions. One of the recentusages of MSCs is in sepsis. G. M. Galstian et al. have recentlyshown that treatment of neutropenic patients with MSCsduring the first hours of septic shock might improve theirshort-term survival, but cannot prevent decease due tolong-term sepsis-related organ dysfunctions [3]. In thepresent special issue, J. Horák et al. have explained in detailthe properties of MSCs and their mechanisms of action inphysiological conditions and in sepsis on their article entitled“Mesenchymal Stem Cells in Sepsis and Associated OrganDysfunction: A Promising Future or Blind Alley?” Theyhave further discussed the beneficial effect of MSCs onthe cardiovascular system as well in sepsis-associatedorgan dysfunction with a special focus on acute kidneyinjury which is the most frequent complication of sepsis.Based on recent literature, they have suggested that MSCswith their anti-inflammatory actions are able to reverse detri-mental effects of endotoxemia in the heart. They have finallyrecommended continued evaluation of the safety of MSCs intreatment of sepsis for further translational research in theform of multicenter projects in several world renownedlaboratories for additional justification and assurance.

Another useful stem/progenitor cell type which isalso commonly used in cell therapy approaches is bonemarrow-derived CD34-positive cells. CD34-positive cellsare a well-characterized population of stem cells which aretraditionally used to reconstitute hematopoietic cells afterradiation or chemotherapy. The capability of CD34-positivecells in the induction of therapeutic angiogenesis is reportedin a variety of animal models and includes pathologicalconditions like myocardial, peripheral, and cerebral ischemiaas well as acute lung injury [4, 5]. Furthermore, differentstudies have shown promising results from treatment withCD34-positive cells in various clinical trials on patients withischemic diseases. Despite increasing numbers of successfulclinical trials which confirm the clinical significance of autol-ogous CD34-positive cell therapy and introduce them aspotent contributors in vascular, cardiovascular, and pulmo-nary repair, the selection of optimal time points, cell dosage,and route of administration still remains unclear. An opti-mized and common evaluation technique on therapeuticefficacy of cell therapy can help to solve these problems.In an interesting in vivo study, T.-H. Huang et al. on theirarticle “Correlation between Therapeutic Efficacy of CD34+

Cell Treatment and Directed In Vivo Angiogenesis inPatients with End-Stage Diffuse Coronary Artery Disease”have investigated the therapeutic efficacy of CD34-positivecell treatment in patients with end-stage diffuse coronaryartery disease as reflected in the rate of angiogenesis/neovascularization pre- and posttreatment with autologousCD34-positive cells. This method is known as “angiographicgrading”. T.-H. Huang et al. have carefully compared theresults of the angiogenic grading method with findings ofthe “directed in vivo angiogenesis assay (DIVAA),” which isa known quantitative assessment technique for angiogenicresponses. They have finally suggested the DIVAA methodas a better and reliable technique than angiographic gradingfor assessing coronary vascularization after CD34-positive

cell treatment. DIVAA has a potential to become routinefor assessment of angiogenic responses in the clinical setting.

Exosomes are cell-derived extracellular vesicles whichcan be found in perhaps all eukaryotic fluids and provide ameans of intercellular communication. They correspond tointraluminal vesicles (ILVs) which are formed within intra-cellular multivesicular bodies (MVBs). ILVs are generatedby invagination of the endosomal membrane via a dependentand/or independent manner to the endosomal sorting com-plexes required for transport. ILVs and exosomes as well willrelease from the cell into the extracellular space upon fusionof MVBs with plasma membrane. The specific contents ofexosomes (e.g., RNAs, lipids, and proteins) which onlyoriginate from the cell cytosol or endosomal compartmentsappear to be as diverse as cell types and are highly dependentto the state of the cell and its changes. Exosomes can bepotentially used as biomarkers for prognosis of differentdiseases and also for therapeutic purposes [6, 7]. J. A.Maring et al. contributed with a review entitled “Myocar-dial Regeneration via Progenitor Cell-Derived Exosomes”where they have broadly described the nature of exosomesin their review article and also explained the current stateof progenitor cell-derived exosomes in experimental ther-apy of heart diseases and their translational potential inmyocardial regeneration.

In agreement with the results of increasing numbers ofclinical trials and various experimental reports, adult stemcell-based therapy is a promising novel approach for thetreatment of various diseases. Biomaterial scaffolds can sup-port the transplantation of stem cell by providing not onlya physical support for transplanted cells but also chemicaland physiological cues for the cells to facilitate tissue regener-ation. The recent development of tissue and biomaterialengineering during last years resulted in a revolution in thefield of regenerative medicine and gives a promising futurein the field of organ regeneration and transplantation whichcan secure a better life quality for the patients. Despitevarious valuable studies in the field of tissue engineering,there is still a long way to find the best and desired biomate-rial scaffolds which should be seeded with sufficient numbersof suitable stem cell types to assemble functional engineeredconstructs that preserve, maintain, and improve damagedtissue or whole organs. Within this special issue, A. O. J.Fakoya et al. published the review article entitled “CurrentTrends in Biomaterial Utilization for CardiopulmonarySystem Regeneration” in which they have broadly discussedthe current natural and synthetic biomaterial scaffolds whichare utilized to regenerate cardiac and pulmonary organs.They have further highlighted advantages and disadvan-tages of each utilized biomaterial scaffold for cardiopulmo-nary system regeneration. This comprehensive review canbe an insight to find out the best choice of biomaterial scaf-folds to generate functional heart and lung tissue batchedfor transplantation.

In summary, this special issue offers a compact overviewof the major findings concerning the impact of stem/progeni-tor cells in health, disease, and treatment of cardiopulmonarydiseases. The recent developments should lead to new scien-tific insights into the function of stem/progenitor cells in the

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context of potential therapeutic applications and next gener-ation stem cell therapies for cardiopulmonary disorders.Combined and continued endeavor between basic, transla-tional, and clinical research will hopefully generate aninnovative and efficient means for the treatment or even cureof devastating cardiopulmonary diseases.

Conflicts of Interest

The authors declare that there is no conflict of interestregarding the publication of this editorial letter in the SPCCHspecial issue of Stem Cells International journal.

Fatemeh SharifpanahHossein A. Ghofrani

Suk Ying TsangHeinrich Sauer

References

[1] T. Le and J. J. H. Chong, “Cardiac progenitor cells for heartrepair,” Cell Death Discovery, vol. 2, no. 1, article 16052, 2016.

[2] L. Bagno, K. E. Hatzistergos, W. Balkan, and J. M. Hare, “Mes-enchymal stem cell-based therapy for cardiovascular disease:progress and challenges,” Molecular Therapy, vol. 26, no. 7,pp. 1610–1623, 2018.

[3] G. M. Galstian et al., “The results of the Russian clinical trial ofmesenchymal stromal cells (MSCs) in severe neutropenicpatients (pts) with septic shock (SS) (RUMCESS trial),” Blood,vol. 126, p. 2220, 2015.

[4] B. C. Lo, M. J. Gold, S. Scheer et al., “Loss of vascular CD34results in increased sensitivity to lung injury,” American Journalof Respiratory Cell and Molecular Biology, vol. 57, no. 6, 2017.

[5] A. R. Mackie and D. W. Losordo, “CD34-positive stem cells: inthe treatment of heart and vascular disease in human beings,”Texas Heart Institute Journal, vol. 38, no. 5, pp. 474–485, 2011.

[6] C. Théry, L. Zitvogel, and S. Amigorena, “Exosomes: composi-tion, biogenesis and function,” Nature Reviews Immunology,vol. 2, no. 8, pp. 569–579, 2002.

[7] E. Van der Pol, A. N. Boing, P. Harrison, A. Sturk, andR. Nieuwland, “Classification, functions, and clinical relevanceof extracellular vesicles,” Pharmacological Reviews, vol. 64,no. 3, pp. 676–705, 2012.

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