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Hénon P, Bischoff N, Dallemand R. Transforming Perspectives in Cardiac Cell Therapy: Hypothesis and Commentary Following Updated Results of a Pilot Study Investigating Very Long-Term Clinical Outcomes in Severe AMI Patients Following Trans-Epicardial Injection of Peripheral Blood CD34 + Cells. Stem Cell Rev Rep 2024; 20:247-257. [PMID: 37861968 PMCID: PMC10799833 DOI: 10.1007/s12015-023-10643-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2023] [Indexed: 10/21/2023]
Abstract
Ischemic heart attack is the leading cause of death worldwide. Ten percent of cases will die within an hour. Of the survivors, around 30% will have suffered a severe infarction which will lead to the irreparable destruction of 1 to 2 billion myocardial cells, causing an irreversible secondary heart failure with a poor prognosis in the short. The heart is a totally differentiated organ with a very low capacity for self-regeneration. No current treatment can prevent this fatal outcome, but only slow it down. For these reasons, cell therapy has generated enormous hope, but achieved somewhat disappointing results, depending on the type/source of cells which were used. From the end of 2002, our group conducted a Pilot study using immuno-selected autologous peripheral-blood (PB) CD34+ cells in a small cohort of patients who had experienced a heart attack with poor prognosis. Three of these patients were immediately considered for heart transplant but lacked a readily available donor. CD34+ cells were trans-epicardially delivered at the end of a coronary artery by-pass graft (CABG) operation without reperfusing the ischemic area, which was performed on a compassionate basis. All but one patient showed a marked and sustained improvement in their cardiac function parameters from the baseline values, associated with both cardiac tissue repair and revascularization, as demonstrated by PetScan examination. The patients' outcomes have been recently updated. Six out of seven patients have survived in good enough conditions for at least 12 years after cell therapy, including those three initially recommended for heart transplant and who have avoided it. Presently, five out of seven patients are still alive with an average follow-up of 17 years (range 16-20 years), which is very unusual after CABG for patients with such a poor initially prognosis.
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Affiliation(s)
- Philippe Hénon
- Institut de Recherche en Hématologie Et Transplantation, Hôpital du Hasenrain, 87 Avenue d'Altkirch, 68100, Mulhouse, France.
- CellProthera SAS, 12 Rue du Parc, 68100, Mulhouse, France.
| | - Nicolas Bischoff
- Département de Chirurgie Cardio-Thoracique, Groupe Hospitalier Régional Mulhouse Sud-Alsace, 20 Rue du Docteur Laënnec, 68100, Mulhouse, France
| | - Robert Dallemand
- Département de Chirurgie Cardio-Thoracique, Groupe Hospitalier Régional Mulhouse Sud-Alsace, 20 Rue du Docteur Laënnec, 68100, Mulhouse, France
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2
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Aries A, Zanetti C, Hénon P, Drénou B, Lahlil R. Deciphering the Cardiovascular Potential of Human CD34 + Stem Cells. Int J Mol Sci 2023; 24:ijms24119551. [PMID: 37298503 DOI: 10.3390/ijms24119551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/17/2023] [Accepted: 05/28/2023] [Indexed: 06/12/2023] Open
Abstract
Ex vivo monitored human CD34+ stem cells (SCs) injected into myocardium scar tissue have shown real benefits for the recovery of patients with myocardial infarctions. They have been used previously in clinical trials with hopeful results and are expected to be promising for cardiac regenerative medicine following severe acute myocardial infarctions. However, some debates on their potential efficacy in cardiac regenerative therapies remain to be clarified. To elucidate the levels of CD34+ SC implication and contribution in cardiac regeneration, better identification of the main regulators, pathways, and genes involved in their potential cardiovascular differentiation and paracrine secretion needs to be determined. We first developed a protocol thought to commit human CD34+ SCs purified from cord blood toward an early cardiovascular lineage. Then, by using a microarray-based approach, we followed their gene expression during differentiation. We compared the transcriptome of undifferentiated CD34+ cells to those induced at two stages of differentiation (i.e., day three and day fourteen), with human cardiomyocyte progenitor cells (CMPCs), as well as cardiomyocytes as controls. Interestingly, in the treated cells, we observed an increase in the expressions of the main regulators usually present in cardiovascular cells. We identified cell surface markers of the cardiac mesoderm, such as kinase insert domain receptor (KDR) and the cardiogenic surface receptor Frizzled 4 (FZD4), induced in the differentiated cells in comparison to undifferentiated CD34+ cells. The Wnt and TGF-β pathways appeared to be involved in this activation. This study underlined the real capacity of effectively stimulated CD34+ SCs to express cardiac markers and, once induced, allowed the identification of markers that are known to be involved in vascular and early cardiogenesis, demonstrating their potential priming towards cardiovascular cells. These findings could complement their paracrine positive effects known in cell therapy for heart disease and may help improve the efficacy and safety of using ex vivo expanded CD34+ SCs.
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Affiliation(s)
- Anne Aries
- Institut de Recherche en Hématologie et Transplantation (IRHT), Hôpital du Hasenrain, 87 Avenue d'Altkirch, 68100 Mulhouse, France
| | - Céline Zanetti
- Institut de Recherche en Hématologie et Transplantation (IRHT), Hôpital du Hasenrain, 87 Avenue d'Altkirch, 68100 Mulhouse, France
| | | | - Bernard Drénou
- Institut de Recherche en Hématologie et Transplantation (IRHT), Hôpital du Hasenrain, 87 Avenue d'Altkirch, 68100 Mulhouse, France
- Groupe Hospitalier de la Région de Mulhouse Sud-Alsace, Hôpital E. Muller, 20 Avenue de Dr Laennec, 68100 Mulhouse, France
| | - Rachid Lahlil
- Institut de Recherche en Hématologie et Transplantation (IRHT), Hôpital du Hasenrain, 87 Avenue d'Altkirch, 68100 Mulhouse, France
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Tang X, Wang Z, Wang J, Cui S, Xu R, Wang Y. Functions and regulatory mechanisms of resting hematopoietic stem cells: a promising targeted therapeutic strategy. Stem Cell Res Ther 2023; 14:73. [PMID: 37038215 PMCID: PMC10088186 DOI: 10.1186/s13287-023-03316-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 03/29/2023] [Indexed: 04/12/2023] Open
Abstract
Hematopoietic stem cells (HSCs) are the common and essential precursors of all blood cells, including immune cells, and they are responsible for the lifelong maintenance and damage repair of blood tissue homeostasis. The vast majority (> 95%) of HSCs are in a resting state under physiological conditions and are only activated to play a functional role under stress conditions. This resting state affects their long-term survival and is also closely related to the lifelong maintenance of hematopoietic function; however, abnormal changes may also be an important factor leading to the decline of immune function in the body and the occurrence of diseases in various systems. While the importance of resting HSCs has attracted increasing research attention, our current understanding of this topic remains insufficient, and the direction of clinical targeted treatments is unclear. Here, we describe the functions of HSCs, analyze the regulatory mechanisms that affect their resting state, and discuss the relationship between resting HSCs and different diseases, with a view to providing guidance for the future clinical implementation of related targeted treatments.
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Affiliation(s)
- Xinyu Tang
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhenzhen Wang
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, 250014, China
- Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jingyi Wang
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, 250014, China
- Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Siyuan Cui
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, 250014, China
- Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ruirong Xu
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, 250014, China.
- Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, China.
- Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Yan Wang
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, 250014, China.
- Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, China.
- Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
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Hénon P, Kowalczyk M, Aries A, Vignon C, Trébuchet G, Lahlil R. Industrialized GMP Production of CD34 + Cells (ProtheraCytes®) at Clinical Scale for Treatment of Ischemic Cardiac Diseases Is Feasible and Safe. Stem Cell Rev Rep 2022; 18:1614-1626. [PMID: 35420389 PMCID: PMC9209364 DOI: 10.1007/s12015-022-10373-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2022] [Indexed: 02/08/2023]
Abstract
Regenerative medicine now needs to pass a crucial turning point, from academic research to the market. Several sources/types of cells have been experimented with, more or less successfully. CD34+ cells have demonstrated multipotent or even pluripotent capacities, making them good candidates for regenerative medicine, particularly for treating heart diseases. Strongly encouraged by the results we achieved in a pilot study using CD34+ stem cells in patients with poor-prognosis acute myocardial infarcts (AMIs), we soon began the development of an industrialized platform making use of a closed automated device (StemXpand®) and a disposable kit (StemPack®) for the large-scale expansion of CD34+ cells with reproducible good manufacturing practice (GMP). This scalable platform can produce expanded CD34+ cells (ProtheraCytes®) of sufficient quality that, interestingly, express early markers of the cardiac and endothelial pathways and early cardiac-mesoderm markers. They also contain CD34+ pluripotent cells characterized as very small embryonic-like stem cells (VSELs), capable of differentiating under appropriate stimuli into different tissue lineages, including endothelial and cardiomyocytic ones.
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Affiliation(s)
| | | | - Anne Aries
- Institut de Recherche en Hématologie et Transplantation, Hôpital du Hasenrain, 87 Avenue d'Altkirch, Mulhouse, France
| | | | | | - Rachid Lahlil
- Institut de Recherche en Hématologie et Transplantation, Hôpital du Hasenrain, 87 Avenue d'Altkirch, Mulhouse, France
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5
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Alloreactivity of Allogeneic Mesenchymal Stem/Stromal Cells and Other Cellular Therapies: A Concise Review. Stem Cells Int 2022; 2022:9589600. [PMID: 35308830 PMCID: PMC8926542 DOI: 10.1155/2022/9589600] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/08/2021] [Accepted: 02/23/2022] [Indexed: 02/08/2023] Open
Abstract
Cellular therapies, deemed live medicine, have brought a wave of new generation biological therapies to treat previously untreatable diseases such as cancers and degenerative diseases like osteoarthritis. These cellular therapies have gained significant recognition in clinical research. The area has been further strengthened with the approval of Chimeric Antigen Receptor added on T cells (CAR-T) therapies by the regulatory authorities USA's Food and Drugs Administration (FDA), European Medical Agency (EMA), the Australian Therapeutic Goods Administration (TGA), and in many countries in 2017 to treat hematological cancers. Another milestone was achieved when allogeneic Mesenchymal Stem Cell- (MSC-) based therapy was approved by the EMA to treat Chrohn's disease in 2018. Allogeneic donor-derived MSC therapies in particular hold great promise and real hope because of their ‘off-the shelf' availability and accessibility for patients in need of urgent treatment. So far, thousands of clinical trials have explored the safety and efficacy of both autologous and allogeneic cell therapies, deeming them safe, however with varying degrees of efficacy. In the current pandemic, clinical trials have begun in many parts of the world to treat severe cases of COVID with MSCs. However, the risk of tissue rejection and the development of undesirable effects due to alloreactivity of allogeneic cells are currently not adequately addressed. Therefore, this warrants careful investigation and detailed reporting of such events by clinical researchers. This review aims at discussing the current landscape of approved allogeneic MSCs along with a few other cellular therapies. We explore any possible reactivity reported to inform the readers of any safety concern and on the efficacy of such therapies.
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Guyonnet L, Detriché G, Gendron N, Philippe A, Latremouille C, Soret L, Capel A, Peronino C, Jansen P, Ivak P, Carpentier A, Mirault T, Netuka I, Guerin CL, Smadja DM. Elevated Circulating Stem Cells Level is Observed One Month After Implantation of Carmat Bioprosthetic Total Artificial Heart. Stem Cell Rev Rep 2021; 17:2332-2337. [PMID: 34622384 DOI: 10.1007/s12015-021-10270-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2021] [Indexed: 11/26/2022]
Abstract
The Aeson® total artificial heart (A-TAH) has been developed as a total heart replacement for patients at risk of death from biventricular failure. We previously described endothelialization of the hybrid membrane inside A-TAH probably at the origin of acquired hemocompatibility. We aimed to quantify vasculogenic stem cells in peripheral blood of patients with long-term A-TAH implantation. Four male adult patients were included in this study. Peripheral blood mononuclear cells were collected before A-TAH implantation (T0) and after implantation at one month (T1), between two and five months (T2), and then between six and twelve months (T3). Supervised analysis of flow cytometry data confirmed the presence of the previously identified Lin-CD133+CD45- and Lin-CD34+ with different CD45 level intensities. Lin-CD133+CD45-, Lin-CD34+CD45- and Lin-CD34+CD45+ were not modulated after A-TAH implantation. However, we demonstrated a significant mobilization of Lin-CD34+CD45dim (p = 0.01) one month after A-TAH implantation regardless of the expression of CD133 or c-Kit. We then visualized data for the resulting clusters on a uniform manifold approximation and projection (UMAP) plot showing all single cells of the live Lin- and CD34+ events selected from down sampled files concatenated at T0 and T1. The three clusters upregulated at T1 are CD45dim clusters, confirming our results. In conclusion, using a flow cytometry approach, we demonstrated in A-TAH-transplanted patients a significant mobilization of Lin-CD34+CD45dim in peripheral blood one month after A-TAH implantation. Using a flow cytometry approach, we demonstrated in A-TAH transplanted patients a significant mobilization of Lin-CD34+CD45dim in peripheral blood one month after A-TAH implantation. This cell population could be at the origin of newly formed endothelial cells on top of hybrid membrane in Carmat bioprosthetic total artificial heart.
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Affiliation(s)
- Léa Guyonnet
- Institut Curie, Cytometry Platform, 75006, Paris, France
| | - Grégoire Detriché
- Innovative Therapies in Haemostasis, INSERM, Université de Paris, 75006, Paris, France
- Vascular Medicine Department and Georges Pompidou European Hospital, AP-HP, 75015, Paris, France
| | - Nicolas Gendron
- Innovative Therapies in Haemostasis, INSERM, Université de Paris, 75006, Paris, France
- Hematology and Biosurgical Research Lab (Carpentier Foundation), AP-HP, Georges Pompidou European Hospital, 75015, Paris, France
| | - Aurélien Philippe
- Innovative Therapies in Haemostasis, INSERM, Université de Paris, 75006, Paris, France
- Hematology and Biosurgical Research Lab (Carpentier Foundation), AP-HP, Georges Pompidou European Hospital, 75015, Paris, France
| | | | - Lou Soret
- Innovative Therapies in Haemostasis, INSERM, Université de Paris, 75006, Paris, France
- Hematology and Biosurgical Research Lab (Carpentier Foundation), AP-HP, Georges Pompidou European Hospital, 75015, Paris, France
| | | | - Christophe Peronino
- Innovative Therapies in Haemostasis, INSERM, Université de Paris, 75006, Paris, France
- Hematology and Biosurgical Research Lab (Carpentier Foundation), AP-HP, Georges Pompidou European Hospital, 75015, Paris, France
- Carmat SA, Vélizy-Villacoublay, France
| | | | - Peter Ivak
- Department of Cardiovascular Surgery, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Alain Carpentier
- Cardiac Surgery Department and Biosurgical Research Lab (Carpentier Foundation), AP-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - Tristan Mirault
- Vascular Medicine Department and Georges Pompidou European Hospital, AP-HP, 75015, Paris, France
- PARCC, INSERM, Université de Paris, 75015, Paris, France
| | - Ivan Netuka
- Department of Cardiovascular Surgery, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Coralie L Guerin
- Institut Curie, Cytometry Platform, 75006, Paris, France
- Innovative Therapies in Haemostasis, INSERM, Université de Paris, 75006, Paris, France
| | - David M Smadja
- Innovative Therapies in Haemostasis, INSERM, Université de Paris, 75006, Paris, France.
- Hematology and Biosurgical Research Lab (Carpentier Foundation), AP-HP, Georges Pompidou European Hospital, 75015, Paris, France.
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7
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Nernpermpisooth N, Sarre C, Barrere C, Contreras R, Luz-Crawford P, Tejedor G, Vincent A, Piot C, Kumphune S, Nargeot J, Jorgensen C, Barrère-Lemaire S, Djouad F. PPARβ/δ Is Required for Mesenchymal Stem Cell Cardioprotective Effects Independently of Their Anti-inflammatory Properties in Myocardial Ischemia-Reperfusion Injury. Front Cardiovasc Med 2021; 8:681002. [PMID: 34616778 PMCID: PMC8488150 DOI: 10.3389/fcvm.2021.681002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 08/24/2021] [Indexed: 11/17/2022] Open
Abstract
Myocardial infarction ranks first for the mortality worldwide. Because the adult heart is unable to regenerate, fibrosis develops to compensate for the loss of contractile tissue after infarction, leading to cardiac remodeling and heart failure. Adult mesenchymal stem cells (MSC) regenerative properties, as well as their safety and efficacy, have been demonstrated in preclinical models. However, in clinical trials, their beneficial effects are controversial. In an experimental model of arthritis, we have previously shown that PPARβ/δ deficiency enhanced the therapeutic effect of MSC. The aim of the present study was to compare the therapeutic effects of wild-type MSC (MSC) and MSC deficient for PPARβ/δ (KO MSC) perfused in an ex vivo mouse model of ischemia-reperfusion (IR) injury. For this purpose, hearts from C57BL/6J mice were subjected ex vivo to 30 min ischemia followed by 1-h reperfusion. MSC and KO MSC were injected into the Langendorff system during reperfusion. After 1 h of reperfusion, the TTC method was used to assess infarct size. Coronary effluents collected in basal condition (before ischemia) and after ischemia at 1 h of reperfusion were analyzed for their cytokine profiles. The dose-response curve for the cardioprotection was established ex vivo using different doses of MSC (3.105, 6.105, and 24.105 cells/heart) and the dose of 6.105 MSC was found to be the optimal concentration. We showed that the cardioprotective effect of MSC was PPARβ/δ-dependent since it was lost using KO MSC. Moreover, cytokine profiling of the coronary effluents collected in the eluates after 60 min of reperfusion revealed that MSC treatment decreases CXCL1 chemokine and interleukin-6 release compared with untreated hearts. This anti-inflammatory effect of MSC was also observed when hearts were treated with PPARβ/δ-deficient MSC. In conclusion, our study revealed that the acute cardioprotective properties of MSC in an ex vivo model of IR injury, assessed by a decreased infarct size at 1 h of reperfusion, are PPARβ/δ-dependent but not related to their anti-inflammatory effects.
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Affiliation(s)
- Nitirut Nernpermpisooth
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.,Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Integrative Biomedical Research Unit, Naresuan University, Phitsanulok, Thailand
| | - Charlotte Sarre
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.,Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Montpellier, France
| | - Christian Barrere
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Rafaël Contreras
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Montpellier, France
| | - Patricia Luz-Crawford
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Montpellier, France.,Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Gautier Tejedor
- MedXCell Science, Institute for Regenerative Medicine and Biotherapy, Montpellier, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Christophe Piot
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.,Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Sarawut Kumphune
- Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Integrative Biomedical Research Unit, Naresuan University, Phitsanulok, Thailand.,Biomedical Engineering Institute, Chiang Mai University, Chiang Mai, Thailand
| | - Joel Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Christian Jorgensen
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | | | - Farida Djouad
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
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8
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Khazaei S, Soleimani M, Tafti SHA, Aghdam RM, Hojati Z. Improvement of Heart Function After Transplantation of Encapsulated Stem Cells Induced with miR-1/Myocd in Myocardial Infarction Model of Rat. Cell Transplant 2021; 30:9636897211048786. [PMID: 34606735 PMCID: PMC8493326 DOI: 10.1177/09636897211048786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Cardiovascular disease is one of the most common causes of death worldwide. Mesenchymal stem cells (MSCs) are one of the most common sources in cell-based therapies in heart regeneration. There are several methods to differentiate MSCs into cardiac-like cells, such as gene induction. Moreover, using a three-dimensional (3D) culture, such as hydrogels increases efficiency of differentiation. In the current study, mouse adipose-derived MSCs were co-transduced with lentiviruses containing microRNA-1 (miR-1) and Myocardin (Myocd). Then, expression of cardiac markers, such as NK2 homeobox 5(Nkx2-5), GATA binding protein 4 (Gata4), and troponin T type 2 (Tnnt2) was investigated, at both gene and protein levels in two-dimensional (2D) culture and chitosan/collagen hydrogel (CS/CO) as a 3D culture. Additionally, after induction of myocardial infarction (MI) in rats, a patch containing the encapsulated induced cardiomyocytes (iCM/P) was implanted to MI zone. Subsequently, 30 days after MI induction, echocardiography, immunohistochemistry staining, and histological examination were performed to evaluate cardiac function. The results of quantitative real -time polymerase chain reaction (qRT-PCR) and immunocytochemistry showed that co-induction of miR-1 and Myocd in MSCs followed by 3D culture of transduced cells increased expression of cardiac markers. Besides, results of in vivo study implicated that heart function was improved in MI model of rats in iCM/P-treated group. The results suggested that miR-1/Myocd induction combined with encapsulation of transduced cells in CS/CO hydrogel increased efficiency of MSCs differentiation into iCMs and could improve heart function in MI model of rats after implantation.
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Affiliation(s)
- Samaneh Khazaei
- Department of Cell and Molecular Biology, Faculty of Biological Science and Technology, Isfahan University, Isfahan, Iran
| | - Masoud Soleimani
- Tissue Engineering and Hematology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.,Tissue Engineering and Nanomedicine Research Center, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Hossein Ahmadi Tafti
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Zohreh Hojati
- Department of Cell and Molecular Biology, Faculty of Biological Science and Technology, Isfahan University, Isfahan, Iran
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9
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Construction of transplantable artificial vascular tissue based on adipose tissue-derived mesenchymal stromal cells by a cell coating and cryopreservation technique. Sci Rep 2021; 11:17989. [PMID: 34504254 PMCID: PMC8429436 DOI: 10.1038/s41598-021-97547-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 08/26/2021] [Indexed: 02/07/2023] Open
Abstract
Prevascularized artificial three-dimensional (3D) tissues are effective biomaterials for regenerative medicine. We have previously established a scaffold-free 3D artificial vascular tissue from normal human dermal fibroblasts (NHDFs) and umbilical vein-derived endothelial cells (HUVECs) by layer-by-layer cell coating technique. In this study, we constructed an artificial vascular tissue constructed by human adipose tissue-derived stromal cells (hASCs) and HUVECs (ASCVT) by a modified technique with cryopreservation. ASCVT showed a higher thickness with more dense vascular networks than the 3D tissue based on NHDFs. Correspondingly, 3D-cultured ASCs showed higher expression of several angiogenesis-related factors, including vascular endothelial growth factor-A and hepatic growth factor, compared to that of NHDFs. Moreover, perivascular cells in ASCVT were detected by pericyte markers, suggesting the differentiation of hASCs into pericyte-like cells. Subcutaneous transplantation of ASCVTs to nude mice resulted in an engraftment with anastomosis of host's vascular structures at 2 weeks after operation. In the engrafted tissue, the vascular network was surrounded by mural-like structure-forming hASCs, in which some parts developed to form vein-like structures at 4 weeks, suggesting the generation of functional vessel networks. These results demonstrated that cryopreserved human cells, including hASCs, could be used directly to construct the artificial transplantable tissue for regenerative medicine.
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10
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Kantapan J, Anukul N, Leetrakool N, Rolin G, Vergote J, Dechsupa N. Iron-Quercetin Complex Preconditioning of Human Peripheral Blood Mononuclear Cells Accelerates Angiogenic and Fibroblast Migration: Implications for Wound Healing. Int J Mol Sci 2021; 22:ijms22168851. [PMID: 34445558 PMCID: PMC8396238 DOI: 10.3390/ijms22168851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023] Open
Abstract
Cell-based therapy is a highly promising treatment paradigm in ischemic disease due to its ability to repair tissue when implanted into a damaged site. These therapeutic effects involve a strong paracrine component resulting from the high levels of bioactive molecules secreted in response to the local microenvironment. Therefore, the secreted therapeutic can be modulated by preconditioning the cells during in vitro culturing. Herein, we investigated the potential use of magnetic resonance imaging (MRI) probes, the "iron-quercetin complex" or IronQ, for preconditioning peripheral blood mononuclear cells (PBMCs) to expand proangiogenic cells and enhance their secreted therapeutic factors. PBMCs obtained from healthy donor blood were cultured in the presence of the iron-quercetin complex. Differentiated preconditioning PBMCs were characterized by immunostaining. An enzyme-linked immunosorbent assay was carried out to describe the secreted cytokines. In vitro migration and tubular formation using human umbilical vein endothelial cells (HUVECs) were completed to investigate the proangiogenic efficacy. IronQ significantly increased mononuclear progenitor cell proliferation and differentiation into spindle-shape-like cells, expressing both hematopoietic and stromal cell markers. The expansion increased the number of colony-forming units (CFU-Hill). The conditioned medium obtained from IronQ-treated PBMCs contained high levels of interleukin 8 (IL-8), IL-10, urokinase-type-plasminogen-activator (uPA), matrix metalloproteinases-9 (MMP-9), and tumor necrosis factor-alpha (TNF-α), as well as augmented migration and capillary network formation of HUVECs and fibroblast cells, in vitro. Our study demonstrated that the IronQ-preconditioning PBMC protocol could enhance the angiogenic and reparative potential of non-mobilized PBMCs. This protocol might be used as an adjunctive strategy to improve the efficacy of cell therapy when using PBMCs for ischemic diseases and chronic wounds. However, in vivo assessment is required for further validation.
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Affiliation(s)
- Jiraporn Kantapan
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Nampeung Anukul
- Division of Transfusion Science, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Nipapan Leetrakool
- Blood Bank Section, Maharaj Nakorn Chiang Mai Hospital, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Gwenaël Rolin
- Inserm Centre d’Investigation Clinique-1431 (Inserm CIC-1431), Centre Hospitalier Régional Universitaire de Besançon, F-25000 Besançon, France;
- Inserm UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Etablissement Français du Sang en Bourgogne Franche-Comté, Université de Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Jackie Vergote
- Laboratoire Signalisation et Transports Ioniques Membranaires (EA 7349), Faculté de Pharmacie, Université de Tours, F-37200 Tours, France;
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand;
- Correspondence: ; Tel.: +66-53-936-022
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11
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Matta A, Nader V, Galinier M, Roncalli J. Transplantation of CD34+ cells for myocardial ischemia. World J Transplant 2021; 11:138-146. [PMID: 34046316 PMCID: PMC8131931 DOI: 10.5500/wjt.v11.i5.138] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/01/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
CD34+ cells are multipotent hematopoietic stem cells also known as endothelial progenitor cells and are useful in regenerative medicine. Naturally, these cells are mobilized from the bone marrow into peripheral circulation in response to ischemic tissue injury. CD34+ cells are known for their high proliferative and differentiation capacities that play a crucial role in the repair process of myocardial damage. They have an important paracrine activity in secreting factors to stimulate vasculogenesis, reduce endothelial cells and cardiomyocytes apoptosis, remodel extracellular matrix and activate additional progenitor cells. Once they migrate to the target site, they enhance angiogenesis, neovascularization and tissue regeneration. Several trials have demonstrated the safety and efficacy of CD34+ cell therapy in different settings, such as peripheral limb ischemia, stroke and cardiovascular disease. Herein, we review the potential utility of CD34+ cell transplantation in acute myocardial infarction, refractory angina and ischemic heart failure.
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Affiliation(s)
- Anthony Matta
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse 31059, France
- Faculty of Medicine, Holy Spirit University of Kaslik, Kaslik 00000, Lebanon
| | - Vanessa Nader
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse 31059, France
- Faculty of Pharmacy, Lebanese University, Beirut 961, Lebanon
| | - Michel Galinier
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse 31059, France
| | - Jerome Roncalli
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse 31059, France
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12
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Mesenchymal Stem Cells for Cardiac Regeneration: from Differentiation to Cell Delivery. Stem Cell Rev Rep 2021; 17:1666-1694. [PMID: 33954876 DOI: 10.1007/s12015-021-10168-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2021] [Indexed: 12/20/2022]
Abstract
Mesenchymal stem cells (MSCs) are so far the most widely researched stem cells in clinics and used as an experimental cellular therapy module, particularly in cardiac regeneration and repair. Ever since the discovery of cardiomyogenesis induction in MSCs, a wide variety of differentiation protocols have been extensively used in preclinical models. However, pre differentiated MSC-derived cardiomyocytes have not been used in clinical trials; highlighting discrepancies and limitations in its use as a source of derived cardiomyocytes for transplantation to improve the damaged heart function. Therefore, this review article focuses on the strategies used to derive cardiomyocytes-like cells from MSCs isolated from three widely used tissue sources and their differentiation efficiencies. We have further discussed the role of MSCs in inducing angiogenesis as a cellular precursor to endothelial cells and its secretory aspects including exosomes. We have then discussed the strategies used for delivering cells in the damaged heart and how its retention plays a critical role in the overall outcome of the therapy. We have also conversed about the scope of the local and systemic modes of delivery of MSCs and the application of biomaterials to improve the overall delivery efficacy and function. We have finally discussed the advantages and limitations of cell delivery to the heart and the future scope of MSCs in cardiac regenerative therapy.
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13
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Semenova E, Grudniak MP, Machaj EK, Bocian K, Chroscinska-Krawczyk M, Trochonowicz M, Stepaniec IM, Murzyn M, Zagorska KE, Boruczkowski D, Kolanowski TJ, Oldak T, Rozwadowska N. Mesenchymal Stromal Cells from Different Parts of Umbilical Cord: Approach to Comparison & Characteristics. Stem Cell Rev Rep 2021; 17:1780-1795. [PMID: 33860454 PMCID: PMC8553697 DOI: 10.1007/s12015-021-10157-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2021] [Indexed: 02/06/2023]
Abstract
Mesenchymal stromal/stem cells (MSCs) are a unique population of cells that play an important role in the regeneration potential of the body. MSCs exhibit a characteristic phenotype and are capable of modulating the immune response. MSCs can be isolated from various tissues such as: bone marrow, adipose tissue, placenta, umbilical cord and others. The umbilical cord as a source of MSCs, has strong advantages, such as no-risk procedure of tissue retrieval after birth and easiness of the MSCs isolation. As the umbilical cord (UC) is a complex organ and we decided to evaluate, whether the cells derived from different regions of umbilical cord show similar or distinct properties. In this study we characterized and compared MSCs from three regions of the umbilical cord: Wharton's Jelly (WJ), the perivascular space (PRV) and the umbilical membrane (UCM). The analysis was carried out in terms of morphology, phenotype, immunomodulation potential and secretome. Based on the obtained results, we were able to conclude, that MSCs derived from distinct UC regions differ in their properties. According to our result WJ-MSCs have high and stabile proliferation potential and phenotype, when compare with other MSCs and can be treated as a preferable source of cells for medical application.
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Affiliation(s)
- Ekaterina Semenova
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Mariusz P Grudniak
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Eugeniusz K Machaj
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Katarzyna Bocian
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Faculty of Biology, Department of Immunology, University of Warsaw, Warsaw, Poland
| | | | - Marzena Trochonowicz
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Igor M Stepaniec
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Magdalena Murzyn
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Karolina E Zagorska
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Dariusz Boruczkowski
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Tomasz J Kolanowski
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Tomasz Oldak
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.
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14
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Girousse A, Mathieu M, Sastourné-Arrey Q, Monferran S, Casteilla L, Sengenès C. Endogenous Mobilization of Mesenchymal Stromal Cells: A Pathway for Interorgan Communication? Front Cell Dev Biol 2021; 8:598520. [PMID: 33490065 PMCID: PMC7820193 DOI: 10.3389/fcell.2020.598520] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 11/18/2020] [Indexed: 12/16/2022] Open
Abstract
To coordinate specialized organs, inter-tissue communication appeared during evolution. Consequently, individual organs communicate their states via a vast interorgan communication network (ICN) made up of peptides, proteins, and metabolites that act between organs to coordinate cellular processes under homeostasis and stress. However, the nature of the interorgan signaling could be even more complex and involve mobilization mechanisms of unconventional cells that are still poorly described. Mesenchymal stem/stromal cells (MSCs) virtually reside in all tissues, though the biggest reservoir discovered so far is adipose tissue where they are named adipose stromal cells (ASCs). MSCs are thought to participate in tissue maintenance and repair since the administration of exogenous MSCs is well known to exert beneficial effects under several pathological conditions. However, the role of endogenous MSCs is barely understood. Though largely debated, the presence of circulating endogenous MSCs has been reported in multiple pathophysiological conditions, but the significance of such cell circulation is not known and therapeutically untapped. In this review, we discuss current knowledge on the circulation of native MSCs, and we highlight recent findings describing MSCs as putative key components of the ICN.
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Affiliation(s)
- Amandine Girousse
- Stromalab, Université de Toulouse, CNRS ERL5311, EFS, INP-ENVT, INSERM U1031, Université Paul Sabatier, Toulouse, France
| | - Maxime Mathieu
- Stromalab, Université de Toulouse, CNRS ERL5311, EFS, INP-ENVT, INSERM U1031, Université Paul Sabatier, Toulouse, France
| | - Quentin Sastourné-Arrey
- Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Sylvie Monferran
- Stromalab, Université de Toulouse, CNRS ERL5311, EFS, INP-ENVT, INSERM U1031, Université Paul Sabatier, Toulouse, France
| | - Louis Casteilla
- Stromalab, Université de Toulouse, CNRS ERL5311, EFS, INP-ENVT, INSERM U1031, Université Paul Sabatier, Toulouse, France
| | - Coralie Sengenès
- Stromalab, Université de Toulouse, CNRS ERL5311, EFS, INP-ENVT, INSERM U1031, Université Paul Sabatier, Toulouse, France
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15
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Hénon P, Lahlil R. CD34+ Stem Cells and Regenerative Medicine. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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