Stem Cells in Clinical Application and Productization E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
- Veröffentlichungsjahr: 2024
Stem cells with self-renewal and multi-lineage differentiation potential have potential for developing medicines for a range of refractory and recurrent disease. This book mainly focuses on the landscape of the biological properties and translational research of stem cells types, including hematopoietic stem cells (HSCs), neural stem cells (NSCs) and mesenchymal stem/stromal cells (MSCs).
The book also introduces readers to the current updates and development prospects of stem cells in singular or combination therapies with advanced biomaterials and technological innovations towards large-scale standardization and productization.
Key Features:
- Introduces readers to stem cell biology and tissue engineering
- Covers innovations in stem cell therapy and biomaterials
- Includes a brief guide to commercialization of stem cell technology
- Includes references for advanced readers
The contents will strengthen the reader’s understanding of stem cell-based therapies. This book is a primer on stem cell and regenerative medicine for a wide readership including, students, healthcare professionals, researchers and general readers.
Readership
Students, healthcare professionals, researchers and general readers.
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FOREWORD
Stem cells possess self-renewal and multi-lineage differentiation potential, which are capable of differentiating into more than 200 types of functional cells in vitro and thus hold promising applications in regenerative medicine. Generally, stem cells can be divided into four types totipotent stem cells (e.g., zygotes), pluripotent stem cells (e.g., embryonic stem cells, induced pluripotent stem cells), multipotent stem cells (e.g., mesenchymal stem/stromal cells, neural stem cells), and unipotent stem cells (e.g., amniotic epithelial stem cells, hematopoietic stem cells).
State-of-the-art renewal has indicated the combination of biomaterials (e.g., hydrogels, hydroxyapatites, nano-materials, scaffolds) with mesenchymal stem/stromal cells (MSCs), which are heterogeneous populations with unique hematopoietic-supporting and immunoregulatory properties for tissue engineering purposes. For decades, we and other investigators have demonstrated the promising prospects of MSC-based tissue engineering in regenerative medicine, and in particular, for the administration of recurrent and refractory disease. Very recently, a number of talented experts took advantage of the biomaterial/MSC composite or scaffolds for applications in osteoarthritis, burn wounds, and refractory wounds associated with diabetic foot as well. Strikingly, the composite or scaffold showed superiority in the continuous improvement of the biological functions of the injured areas over biomaterials or MSCs, respectively. Therewith, stem cells, and biomaterials are recognized as “seeds” and “soils”, which are of equal importance for tissue engineering. Collectively, stem cell and biomaterial-based tissue engineering is a core frontier area for disease remodeling and the accompanied regenerative medicine in the future.
Therewith, in this book, Professor Leisheng Zhang in our team and the coauthors have summarized the latest updates of biomaterial/stem cell composites in tissue engineering and put forward the hotspot issues in the future including 3D printing, biomaterial/MSC-exosomes in preclinical and clinical applications.
PREFACE
Stem cells with self-renewal and multi-lineage differentiation potential have highlighted regenerative medicine for diverse refractory and recurrent disease administration. This book mainly focuses on the landscape of the biological properties and translational research of representative types of stem cells, including hematopoietic stem cells (HSCs), neural stem cells (NSCs), and mesenchymal stem/stromal cells (MSCs). Meanwhile, we are aiming to introduce the latest updates and development prospects of stem cells alone or in combination with advanced biomaterials and technological innovations toward large-scale standardization and productization. Collectively, the content will help enlighten the understanding and further development of stem cell-based innovative medicine and healthcare.
List of Contributors
The Historical Overview of Stem Cells
Leisheng Zhang1,2,3,4,*,#,Hao Yu5,6,7,#,Wenjing Du5,6,7,#,Shuang Chen8,Yuan- guang Zhao8,Jun Yao9,*,Cunrong Chen10Abstract
Stem cells of hierarchical clustering have emerged as alternative and promising sources for tissue engineering and regenerative medicine. Owing to the unique self-renewal and multi-lineage differentiation attributes, stem cell-based cytotherapy has evoked great expectations in handling numerous refractory and recurrent diseases. Of note, quality control (QC), good manufacturing practice (GMP), and guidelines for stem cells and the derivations are prerequisites for evaluating the safety and efficacy of stem cell-based remedies. In this book, we principally focus on the definition, classification, signatures and functions, safety and efficacy of stem cells, together with the core concerns upon stem cell-based clinical applications and investigational new drug (IND) and new drug application (NDA). Collectively, this
book will effectively benefit the novel stem cell-based tissue engineering and regenerative medicine.
Introduction
Stem cells are unique cell types of undifferentiated population, which are characterized by self-renewal and multi-lineage differentiation features, and thus hold promising prospects in tissue engineering and regenerative medicine [1]. State-of-the-art renewal has indicated the involvement of stem cells in a variety of physiological and pathological processes. On the one hand, numerous preclinical and clinical investigations have highlighted the therapeutic prospects in multiple refractory and recurrent disease administration, including hematological and circulatory diseases (e.g., acquired aplastic anemia, acute lymphoblastic leukemia, graft-versus-host disease, acute myocardial infarction) [2-5], urogenital diseases (e.g., premature ovarian failure, Turner's syndrome, intrauterine adhesion, thin endometrium, male erectile dysfunction, female stress urinary incontinence, interstitial cystitis) [6-10], neurological disorders (e.g., Parkinson's disease, Alzheimer's disease, cerebral stroke, infantile cerebral palsy, spinal cord injury) [11-16], motor system diseases (e.g., osteoarthritis, meniscus injury, osteone- crosis of the femoral head, critical limb ischemia) [17-19], respiratory diseases (e.g., bronchopneumonia, chronic obstructive pulmonary disease, anaphylactic rhinitis, and even COVID-19-induced acute lung injury and acute respiratory distress syndrome) [20-24], cutaneous diseases (e.g., decubitus, refractory wounds, allergic dermatitis) [25-27], immune diseases (e.g., systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis) [28-32], endocrine and metabolic diseases (e.g., diabetes and complications, osteoporosis, hyperuricemia and gout) [33-36], and digestive diseases (e.g., decompensated liver cirrhosis, acute colitis, chronic acute liver failure, Crohn's disease, ulcerative colitis) [37-44]. On the other hand, we and other investigators in the field have also devoted to dissecting the potential pathogenicity of stem cells via secretion, dysimmuno- modulation, and providing a constitutive microenvironment [20, 38, 45]. For instance, we recently reported the multifaceted variations in the biological phenotypes and transcriptomic features of bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) in patients with acquired aplastic anemia and acute myeloid leukemia [45, 46].
Despite the detailed information of the mode of action of stem cells is still far from satisfaction, yet the overall ways of function have been extensively described, including direct-differentiation, trans-differentiation, dedifferentiation, autocrine and paracrine (e.g., exosomes, small microvesicles, cytokines, anti-inflammatory factors), bidirectional immunomodulation, and constitutive microenvironments [1, 13, 47-49]. For instance, Yuan et al. put forward the therapeutic applications and the concomitant “SMART” principles (including self-renewal, multi-lineage differentiation, apoptosis, rest, and trafficking) of hematopoietic stem cells (HSCs) for hematologic malignancy administration [50]. Instead, Zhao et al. highlighted the underlying mechanism of HSC-based cytotherapy for continuous blood cell generation via orchestrating cell proliferation, self-renewal, and cell differentiation in the microenvironment [51]. As to MSC-based remedies, we and the colleagues also verify the way of action such as differentiation, secretion, hematopoietic-supporting effect and bidirectional immunoregulation [4, 18, 20].
In this chapter, we mainly focus on the multifaceted characterization of the definition, classification, and the features of stem cells, which will supply overwhelming new references for further understanding the historical overview as well as dissecting the fundamental and clinical investigation of stem cell-based tissue engineering and regenerative medicine.
The Definition and History of Stem Cells
In 1868, Ernst Haeckel and the colleagues originally put forward the definition of “Stammzelle” (stem cells) for the description of the ancestor unicellular organisms for the evolvement of all multicellular organisms, who were also the pioneering proponent of the “Anthropozoic Age”concept [52, 53]. In 1902, hematopoietic progenitor cells (HPCs) were identified from bone marrow, and HPC-based transplantation was accomplished for aplastic anemia treatment in 1939 [54]. In 1957, E. Donnall Thomas reported the first allogeneic transplantation of hematopoietic stem cell transplantation (HSCT) by combining the unfractionated mononuclear population with immune suppressive regimens [55-57]. In 1968, Friendenstein and the collaborators verified the distinctions between HSCs and stromal cells in the bone marrow environment, which were further named “mesenchymal stem/stromal cells” by Arnold I Caplan et al in 1991 [58, 59]. In 1990s and 2000s, pluripotent stem cells (PSCs) including embryonic stem cells (ESCs) and induced PSCs (iPSCs) were identified with the aid of OSKM factor (also known as “Yamanaka factors”, including OCT4, SOX2, KLF4, and c-MYC)-based reprogramming strategy, respectively (Fig. 1) [60-64].
Fig. (1)) The history and cell source of stem cell-based cytotherapy [54].The Characteristics and Biology of Stem Cells
As referred above, stem cells are populations with self-renewal and multi-lineage differentiation properties, yet vary in developmental potency and the concomitant range of specialized progeny [65]. Generally, PSCs have been considered with potency for generating three germ layers (e.g., ectoderm, endoderm, mesoderm) and all organism cells, whereas multipotent stem cells and unipotent stem cells can only regenerate specific tissues or lineages instead [65]. Distinguished from the aforementioned subtypes of stem cells, totipotent stem cells (e.g., spermatovum, gastrula stage cells, morula stage cells) are adequate to generate accessory tissue of embryos such as umbilical cord, placenta, amniotic membrane and amniotic fluid.
Currently, a variety of strategies have been involved and developed to define stem cell potency from the aspects of functional analyses, transcriptional expression pattern, single-cell heterogeneity, hallmarks of pluripotency, epigenetic and metabolic status [65]. For instance, PSCs with the robust expression of pluripotency-associated biomarkers (e.g., POU5F1, SOX2, and NANOG), while HSCs and MSCs with the abundant expression of hematopoiesis-related (e.g., CD34, CD45, CD43) and mesenchymal-related (e.g., CD44, CD73, CD105) surface biomarkers, respectively [4, 67, 68]. Murtha M, et al. took advantage of
the comparative FAIRE-seq analysis and verified the distinguishing features in the chromatin structure between ground primed- and state- pluripotent cells [69]. Instead, Tong et al. and Wang et al. reported the heterogeneity of HSCs and megakaryocytes by utilizing the single-cell transcriptomic analysis, respectively [70, 71].
Of note, one of the current research hotspots has turned to disclose the heterogeneity of stem cells and the specific subpopulations to better fulfill the requirements of tissue engineering and regenerative medicine. For instance, we and Zhang et al. respectively demonstrated multidimensional alterations and even contradictory outcomes of MSC-based cytotherapy for acute GvHD (aGvHD) and acute liver failure (ALF) due to the otherness in cell sources, which collectively indicated the impact of the heterogeneity of stem cells upon therapeutic effect [4, 72]. Therewith, more and more studies emphasize the necessity of identifying novel surface biomarkers for dissecting unique subpopulations with potentially specific bioactivity. For instance, Battula et al. and Studle et al. reported the MSCA-1+CD56+ subset and CD56+ subset of MSCs with predominant differentiation bias towards pancreatic-like islets and chondrocytes over those negative counterparts, respectively [73, 74]. Similarly, Du and the colleagues verified that the content of VCAM-1+ subpopulation varied among BM-MSCs, umbilical cord-derived MSCs (UC-MSCs), and placenta chorionic villi-derived MSCs (CV-MSCs), which displayed preferable pro-angiogenic activity in vitro and in vitro when compared with the VCAM-1- subset [75]. Interestingly, with the aid of cytokine cocktail-based programming, we established a high-efficiency procedure for VCAM-1+ UC-MSCs preparation within 48 hours, and the indicated cells revealed enhanced pro-angiogenic activity and efficacy for aplastic anemia mice over the VCAM-1+ subset [3]. Very recently, we further demonstrated the preferable outcomes of cerebral infarction in rats and acute lung injury in mice, respectively [76, 77]. Overall, with the aid of systematic and detailed dissection of the heterogeneity in preclinical and clinical investigations, the potential variations and contradictoriness of stem cell-based cytotherapy can be hopefully well resolved.
The Classification of Stem Cells
As mentioned above, stem cells and derivations (e.g., exosomes, small extracellular vesicles) are advantaged sources with unique superiorities for tissue engineering and the resultant regenerative medicine [32, 78, 79]. Generally, according to the aforementioned differentiation potential, stem cells can be divided into totipotent stem cells (e.g., germ cells), pluripotent stem cells (e.g., embryonic stem cells, induced pluripotent stem cells), multipotent stem cells (e.g., mesenchymal stem/stromal cells, amniotic stem cells), unipotent stem cells (e.g., neural stem cells, hematopoietic stem cells, amniotic epithelial stem cells), and even the newly identified post-embryonic sub-totipotent stem cells (a hierarchical system of mesenchymal stem/stromal cells) [78, 80-82]. Meanwhile, stem cells can be classified into natural stem cells (e.g., embryonic stem cells, perinatal stem cells, and adult tissue-derived stem cells) and artificial stem cells (e.g., haploid stem cells, induced pluripotent stem cells, and nuclear transplanted stem cells) according to the origins [64, 79]. For instance, perinatal stem cells can be divided into umbilical cord-derived MSCs, umbilical cord blood-derived MSCs, amniotic epithelial stem cells (AESCs), amniotic mesenchymal stem cells (AMSCs), amniotic fluid-derived MSCs, placenta-derived stem cells, and placental chorionic villi-derived MSCs (CV-MSCs) [39, 75, 80, 82, 83].
The Safety and Efficacy of Stem Cells
Due to the unique attributes of stem cells, the safety and efficacy issues after transplantation are the prerequisites of stem cell-based cytotherapy before large-scale clinical application. In particular, PSCs including ESCs and iPSCs are capable of differentiating into all types of functional cells and thus the safety issue has been considered as a long-disturbing problem in the field [38, 84, 85]. Meanwhile, numerous pending questions also hamper the PSC-based translational medicine due to the intrinsic attributes, including technological, ethical, and regulatory complications [86]. In details, the variations and difficulties in clinically relevant features further hamper the large-scale application of PSC-based cytotherapy, such as generation methods for the development of autologous clinical-grade PSC lines, high-efficient procedures and good manufacturing practices (GMP) for cost-effective generation of functional cells, propensity to epigenetic abnormalities or genetic mutations, and the tumorigenicity [86].
Different from the aforementioned PSCs, MSCs of different origins reveal reliable hypoimmunogenicity and thus satisfy the demands for autologous and allogeneic infusion in tissue engineering and regenerative medicine, which therewith hold more robust prospects for conquering the recurrent and refractory diseases. Interestingly, Zhao et al. recently provided systematic and detailed description of the biological features (e.g., cellular immunophenotyping, tri-lineage differentiation potential, hematopoietic-supporting effect, efficacy upon aGvHD mice) and tumorigenicity (e.g., proto-oncogenes, tumor suppressor genes, chromosome structure, in vivo tumor formation test) of UC-MSCs at various passages, which collectively demonstrated the conservations and variations in continuous passages upon the safety and efficacy of UC-MSCs [4].
It’s noteworthy that pioneering investigators in the field have turned their attention and aimed to solve the concomitant problems in safety and efficacy by releasing consensus and general requirements for stem cells [87]. For instance, the Chinese Society for Stem Cell Research (CSSCR) issued the first set of general guidelines for stem cell research and production in China named “General requirements for stem cells”, which collectively specified the classification, quality requirements, ethical requirements, detection control requirements, quality control requirements, and waste disposal requirements of stem cells [87]. Meanwhile, Hao et al. and Chen et al. also respectively put forward general guidelines for human ESCs (hESCs) and MSCs, which were applicable to the quality control for the aforementioned stem cell subtypes and thus benefited the international standardization [88, 89]. Very recently, Nan and the colleagues highlighted the requirements for human haematopoietic stem/progenitor cells (HSPCs), including instructions for usage, technical requirements, inspection rules and methods, packaging requirements, labeling requirements, storage and transportation requirements [90].
Notably, Zhao et al. introduced the principles of clinical grade MSCs for investigational new drug (IND) in 2021 from the aspect of guidance, regulations, processes, quality management, pre-IND meeting as well as IND application for obtaining permission to launch clinical trials in China (Fig. 2) [66]. In this review article, they discussed the major intermediate stages during MSC product development in detail, such as the basic research stage (e.g., cell isolation and purification, cell expansion, cell culture medium development, cell characteristics analysis, and the underlying mechanisms of action for specific indications), pharmacy stage (e.g., product testing and release, chemistry manufacturing control, and stability programs), pharmacology stage (e.g., definition of targeted indications and route of administration, solidification of anticipated mechanism of action, identification of biologically active dose, determination of efficacy, demonstration of safety and pharmacokinetics), toxicology stage (e.g., a single dose toxicity test, reproductive toxicity, tumorigenicity research, immunotoxicity test, repeated administration toxicity test, antigenicity test, genetic toxicity, and local tolerance), IND application stage (e.g., pre-IND meeting, IND application filing, IND submission), and clinical trials stage (e.g., exploratory clinical trials, confirmatory clinical trials) [66].
In 2022, we and the collaborators further put forward the necessity and principles of quality control (QC) of UC-MSCs for acute GvHD (aGvHD) and chronic GvHD (cGvHD) during investigational new drug (IND) administration in China, which assure the consistency and feasibility of the safety and quality of UC-MSCs [2]. Furthermore, we emphasized the pivotal role of GMP for safety and efficacy evaluation during the large-scale preparation of therapeutic MSC drugs for carbon tetrachloride (CCl4)-induced acute-on-chronic liver failure (ACLF) [37]. Taken together, the published general requirements of guidelines and standards will benefit the decoding of the safety and efficacy assessment of stem cell-based tissue engineering and regenerative medicine in future.
Fig. (2)) Content and flow chart of MSC product development [66].Conclusion
Stem cells are unique cell types with self-renewal and multi-lineage differentiation properties, which thus have potential application prospects in conquering refractory and recurrent diseases as well as the concomitant tissue engineering and regenerative medicine. To better fulfill the aims of clinical application and investigational new drug application, it is of critical importance in systematic and detailed illustration of the principles and guidelines for biological features and the underlying mechanism. Overall, before large-scale application, the assessment of the safety and efficacy of stem cells are prerequisites for stem cell-based remedies and product development in future.
Abbreviations
PSCsPluripotent stem cellsESCsEmbryonic stem cellsiPSCsInduced pluripotent stem cellsMSCsMesenchymal stem/stromal cellsASCsAmniotic stem cellsAAAplastic anemiaALLAcute lymphoblastic leukemiaAESCsAmniotic epithelial stem cellsAMSCsAmniotic mesenchymal stem cellsGvHDGraft-versus-host diseaseAMIAcute myocardial infarctionPOFPremature ovarian failurePDParkinson's diseaseADAlzheimer's diseaseSCISpinal cord injuryOAOsteoarthritisONFHOsteonecrosis of the femoral headCLICritical limb ischemiaCOPDChronic obstructive pulmonary diseaseARAnaphylactic rhinitisALIAcute lung injuryARDSAcute respiratory distress syndromeADAllergic dermatitisSSSystemic sclerosisSLESystemic lupus erythematosusRARheumatoid arthritisACLFAcute-on-chronic liver failureCDCrohn's diseaseUCUlcerative colitisBM-MSCsBone marrow-derived MSCsUC-MSCsUmbilical cord-derived MSCsHPCsHematopoietic progenitor cellsHSCTHematopoietic stem cell transplantationaGvHDAcute GvHDcGvHDChronic GvHDALFAcute liver failureCV-MSCsChorionic villi-derived MSCsGMPGood manufacturing practicesCSSCRChinese Society for Stem Cell ResearchHSPCsHaematopoietic stem/progenitor cellsINDInvestigational new drugQCQuality controlCCl4Carbon tetrachlorideACKNOWLEDGEMENTS
This work was supported by grants from the National Natural Science Foundation of China (82260031, 31900460), Jiangxi Provincial Natural Science Foundation (20224BAB206077, 20212BAB216073), Science and technology projects of Guizhou Province (QKH-J-ZK[2021]-107, Zhukehetong ([2019]9-1-1), Qiankehejichu-2K[2023]), the project Youth Fund supported by Shandong Provincial Natural Science Foundation (ZR2020QC097), Natural Science Foundation of Fujian Province (2020J01649), Fujian Provincial Ministerial Finance Special Project (2021XH018), Medical Innovation Project of Fujian Provincial Health and Health Commission (2019-CX-21), Project funded by China Postdoctoral Science Foundation (2023M730723, 2019M661033), Postdoctoral Program of Natural Science Foundation of Gansu Province (23JRRA1319), Jiangxi Provincial leading Talent of “Double Thousand Plan” (jxsq2023102017), Gansu Provincial Hospital Intra-Hospital Research Fund Project (22GSSYB-6), The 2022 Master/Doctor/Postdoctoral program of NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor (NHCDP2022004, NHCDP2022008), Science and Technology Program of Shangrao City (2020AB002, 2020G002, 2020K003, 2021F013, 2022A001, 2022AB003, 2022A001), the Key Laboratory of Gastrointestinal Tumor Diagnosis and the Treatment of National Health and Health Commission (2019PT320005), and The 2021 Central-Guided Local Science and Technology Development Fund (ZYYDDFFZZJ-1). The coauthors also thank the members of the Hefei Institute of Physical Science at the Chinese Academy of Sciences, Gansu Province of Gansu Provincial Hospital, and The First Affiliated Hospital of Shandong First Medical University for their suggestions. The authors would like to acknowledge the authors Hanjing Xie and Shuling Wang for their contribution to the revision of the manuscript.
