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Human mesenchymal stem cell secretomes: Factors affecting profiling and challenges in clinical application

Noor Azlan NAB, Vitus V, Nor Rashid N, Nordin F, Tye GJ, Wan Kamarul Zaman WS

Cell Tissue Res, 2024 Mar;395(3):227-250.
PMID: 38244032 DOI: 10.1007/s00441-023-03857-4

The promising field of regenerative medicine is thrilling as it can repair and restore organs for various debilitating diseases. Mesenchymal stem cells are one of the main components in regenerative medicine that work through the release of secretomes. By adopting the use of the secretome in cell-free-based therapy, we may be able to address the challenges faced in cell-based therapy. As one of the components of cell-free-based therapy, secretome has the advantage of a better safety and efficacy profile than mesenchymal stem cells. However, secretome has its challenges that need to be addressed, such as its bioprocessing methods that may impact the secretome content and its mechanisms of action in clinical settings. Effective and standardization of bioprocessing protocols are important to ensure the supply and sustainability of secretomes for clinical applications. This may eventually impact its commercialization and marketability. In this review, the bioprocessing methods and their impacts on the secretome profile and treatment are discussed. This improves understanding of its fundamental aspects leading to potential clinical applications.

Matched MeSH terms: Regenerative Medicine/methods
Engineering physical microenvironment for stem cell based regenerative medicine

Han YL, Wang S, Zhang X, Li Y, Huang G, Qi H, et al.

Drug Discov Today, 2014 Jun;19(6):763-73.
PMID: 24508818 DOI: 10.1016/j.drudis.2014.01.015

Regenerative medicine has rapidly evolved over the past decade owing to its potential applications to improve human health. Targeted differentiations of stem cells promise to regenerate a variety of tissues and/or organs despite significant challenges. Recent studies have demonstrated the vital role of the physical microenvironment in regulating stem cell fate and improving differentiation efficiency. In this review, we summarize the main physical cues that are crucial for controlling stem cell differentiation. Recent advances in the technologies for the construction of physical microenvironment and their implications in controlling stem cell fate are also highlighted.

Matched MeSH terms: Regenerative Medicine/methods*
Generation of induced pluripotent stem cells by a polycistronic lentiviral vector in feeder- and serum- free defined culture

Al Abbar A, Nordin N, Ghazalli N, Abdullah S

Tissue Cell, 2018 Dec;55:13-24.
PMID: 30503056 DOI: 10.1016/j.tice.2018.09.004

Induced pluripotent stem cells (iPSCs) have great potentials for regenerative medicine. However, serious concerns such as the use of the viral-mediated reprogramming strategies and exposure of iPSCs to animal products from feeder cells and serum-containing medium have restricted the application of iPSCs in the clinics. Therefore, the generation of iPSCs with minimal viral integrations and in non-animal sourced and serum-free medium is necessary. In this report, a polycistronic lentiviral vector carrying Yamanaka's factors was used to reprogram mouse fibroblasts into iPSCs in feeder- and xeno-free culture environment. The generated iPSCs exhibited morphology and self-renewal properties of embryonic stem cells (ESCs), expression of specific pluripotent markers, and potentials to differentiate into the three-major distinct specialized germ layers in vitro. The iPSCs were also shown to have the potential to differentiate into neural precursor and neurons in culture, with greater than 95% expression of nestin, Pax6 and βIII-tubulin. This body of work describes an alternative method of generating iPSCs by using polycistronic lentiviral vector that may minimize the risks associated with viral vector-mediated reprogramming and animal derived products in the culture media.

Matched MeSH terms: Regenerative Medicine/methods
Current attempts to implement microRNA-based diagnostics and therapy in cardiovascular and metabolic disease: a promising future

Thanikachalam PV, Ramamurthy S, Wong ZW, Koo BJ, Wong JY, Abdullah MF, et al.

Drug Discov Today, 2018 Mar;23(3):460-480.
PMID: 29107764 DOI: 10.1016/j.drudis.2017.10.020

MicroRNAs (miRNAs) are small, noncoding RNAs regulating gene expression at the post-translational level. miRNA-based therapeutic agents are important because of the functionality of miRNAs in regulating lipid and glucose metabolism and their role in the pathogenesis of metabolic disorders such as diabetes and obesity, where dysregulation leads to disease; they are also important in angiogenesis. miRNAs additionally serve as biomarkers in the diagnosis, prognosis and risk assessment of disease and in monitoring the response to treatment. Here, we provide a brief overview of progress in miRNA-based therapeutics in the preclinical and clinical setting and highlight the novel outcomes and opportunities in the diagnosis and treatment of metabolic conditions. In addition, we present the role of miRNAs in stem cell therapy which could have great potential in regenerative medicine.

Matched MeSH terms: Regenerative Medicine/methods
Identification and Characterization of Intraoral and Dermal Fibroblasts Revisited

Mohd Nor NH, Berahim Z, Azlina A, Mokhtar KI, Kannan TP

Curr Stem Cell Res Ther, 2017;12(8):675-681.
PMID: 28969579 DOI: 10.2174/1574888X12666170929124621

BACKGROUND: Fibroblasts are the common cells used in clinical regenerative medicine and dentistry. These cells are known to appear heterogeneous in vivo. Previous studies have only investigated the biological properties of these cell subpopulations in vitro. Despite sharing similarity in their spindle-shaped appearance, previous literatures revealed that they play distinguished functional and biological activities in the body.
OBJECTIVE: This paper highlights the similarities and differences among these cell subpopulations, particularly between intraoral fibroblasts (human periodontal ligament, gingival and oral mucosa fibroblasts) and dermal fibroblasts based on several factors including their morphology, growth and proliferation rate.
RESULTS: It could be suggested that each subpopulation of fibroblasts demonstrate different positionspecified gene signatures and responses towards extracellular signals. These dissimilarities are crucial to be taken into consideration to employ specific methodologies in stimulating these cells in vivo.
CONCLUSION: A comparison of the characteristics of these cell subpopulations is desired for identifying appropriate cellular applications.

Matched MeSH terms: Regenerative Medicine/methods
The Advancement of Biomaterials in Regulating Stem Cell Fate

Hiew VV, Simat SFB, Teoh PL

Stem Cell Rev Rep, 2018 Feb;14(1):43-57.
PMID: 28884292 DOI: 10.1007/s12015-017-9764-y

Stem cells are well-known to have prominent roles in tissue engineering applications. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can differentiate into every cell type in the body while adult stem cells such as mesenchymal stem cells (MSCs) can be isolated from various sources. Nevertheless, an utmost limitation in harnessing stem cells for tissue engineering is the supply of cells. The advances in biomaterial technology allows the establishment of ex vivo expansion systems to overcome this bottleneck. The progress of various scaffold fabrication could direct stem cell fate decisions including cell proliferation and differentiation into specific lineages in vitro. Stem cell biology and biomaterial technology promote synergistic effect on stem cell-based regenerative therapies. Therefore, understanding the interaction of stem cell and biomaterials would allow the designation of new biomaterials for future clinical therapeutic applications for tissue regeneration. This review focuses mainly on the advances of natural and synthetic biomaterials in regulating stem cell fate decisions. We have also briefly discussed how biological and biophysical properties of biomaterials including wettability, chemical functionality, biodegradability and stiffness play their roles.

Matched MeSH terms: Regenerative Medicine/methods
Fulltext Recent Advances in Biopolymeric Composite Materials for Tissue Engineering and Regenerative Medicines: A Review

Aslam Khan MU, Abd Razak SI, Al Arjan WS, Nazir S, Sahaya Anand TJ, Mehboob H, et al.

Molecules, 2021 Jan 25;26(3).
PMID: 33504080 DOI: 10.3390/molecules26030619

The polymeric composite material with desirable features can be gained by selecting suitable biopolymers with selected additives to get polymer-filler interaction. Several parameters can be modified according to the design requirements, such as chemical structure, degradation kinetics, and biopolymer composites' mechanical properties. The interfacial interactions between the biopolymer and the nanofiller have substantial control over biopolymer composites' mechanical characteristics. This review focuses on different applications of biopolymeric composites in controlled drug release, tissue engineering, and wound healing with considerable properties. The biopolymeric composite materials are required with advanced and multifunctional properties in the biomedical field and regenerative medicines with a complete analysis of routine biomaterials with enhanced biomedical engineering characteristics. Several studies in the literature on tissue engineering, drug delivery, and wound dressing have been mentioned. These results need to be reviewed for possible development and analysis, which makes an essential study.

Matched MeSH terms: Regenerative Medicine/methods*
Fulltext Hypoxic culture conditions as a solution for mesenchymal stem cell based regenerative therapy

Haque N, Rahman MT, Abu Kasim NH, Alabsi AM

ScientificWorldJournal, 2013;2013:632972.
PMID: 24068884 DOI: 10.1155/2013/632972

Cell-based regenerative therapies, based on in vitro propagation of stem cells, offer tremendous hope to many individuals suffering from degenerative diseases that were previously deemed untreatable. Due to the self-renewal capacity, multilineage potential, and immunosuppressive property, mesenchymal stem cells (MSCs) are considered as an attractive source of stem cells for regenerative therapies. However, poor growth kinetics, early senescence, and genetic instability during in vitro expansion and poor engraftment after transplantation are considered to be among the major disadvantages of MSC-based regenerative therapies. A number of complex inter- and intracellular interactive signaling systems control growth, multiplication, and differentiation of MSCs in their niche. Common laboratory conditions for stem cell culture involve ambient O₂ concentration (20%) in contrast to their niche where they usually reside in 2-9% O₂. Notably, O₂ plays an important role in maintaining stem cell fate in terms of proliferation and differentiation, by regulating hypoxia-inducible factor-1 (HIF-1) mediated expression of different genes. This paper aims to describe and compare the role of normoxia (20% O₂) and hypoxia (2-9% O₂) on the biology of MSCs. Finally it is concluded that a hypoxic environment can greatly improve growth kinetics, genetic stability, and expression of chemokine receptors during in vitro expansion and eventually can increase efficiency of MSC-based regenerative therapies.

Matched MeSH terms: Regenerative Medicine/methods
Microenvironmental factors involved in human amnion mesenchymal stem cells fate decisions

Syva SH, Ampon K, Lasimbang H, Fatimah SS

J Tissue Eng Regen Med, 2017 02;11(2):311-320.
PMID: 26073746 DOI: 10.1002/term.2043

Human amnion mesenchymal stem cells (HAMCs) show great differentiation and proliferation potential and also other remarkable features that could serve as an outstanding alternative source of stem cells in regenerative medicine. Recent reports have demonstrated various kinds of effective artificial niche that mimic the microenvironment of different types of stem cell to maintain and control their fate and function. The components of the stem cell microenvironment consist mainly of soluble and insoluble factors responsible for regulating stem cell differentiation and self-renewal. Extensive studies have been made on regulating HAMCs differentiation into specific phenotypes; however, the understanding of relevant factors in directing stem cell fate decisions in HAMCs remain underexplored. In this review, we have therefore identified soluble and insoluble factors, including mechanical stimuli and cues from the other supporting cells that are involved in directing HAMCs fate decisions. In order to strengthen the significance of understanding on the relevant factors involved in stem cell fate decisions, recent technologies developed to specifically mimic the microenvironments of specific cell lineages are also reviewed. Copyright © 2015 John Wiley & Sons, Ltd.

Matched MeSH terms: Regenerative Medicine/methods*
Potential applications of engineered nanoparticles in medicine and biology: an update

Rudramurthy GR, Swamy MK

J Biol Inorg Chem, 2018 Dec;23(8):1185-1204.
PMID: 30097748 DOI: 10.1007/s00775-018-1600-6

Nanotechnology advancements have led to the development of its allied fields, such as nanoparticle synthesis and their applications in the field of biomedicine. Nanotechnology driven innovations have given a hope to the patients as well as physicians in solving the complex medical problems. Nanoparticles with a size ranging from 0.2 to 100 nm are associated with an increased surface to volume ratio. Moreover, the physico-chemical and biological properties of nanoparticles can be modified depending on the applications. Different nanoparticles have been documented with a wide range of applications in various fields of medicine and biology including cancer therapy, drug delivery, tissue engineering, regenerative medicine, biomolecules detection, and also as antimicrobial agents. However, the development of stable and effective nanoparticles requires a profound knowledge on both physico-chemical features of nanomaterials and their intended applications. Further, the health risks associated with the use of engineered nanoparticles needs a serious attention.

Matched MeSH terms: Regenerative Medicine/methods
Allogeneic and autologous mode of stem cell transplantation in regenerative medicine: which way to go?

Mamidi MK, Dutta S, Bhonde R, Das AK, Pal R

Med Hypotheses, 2014 Dec;83(6):787-91.
PMID: 25456787 DOI: 10.1016/j.mehy.2014.10.010

Stem cell transplantation is a generic term covering different techniques. However there is argument over the pros and cons of autologous and allogeneic transplants of mesenchymal stem cells (MSCs) for regenerative therapy. Given that the MSCs have already been proven to be safe in patients, we hypothesize that allogeneic transplantation could be more effective and cost-effective as compared to autologous transplantation specifically in older subjects who are the likely victims of degenerative diseases. This analysis is based on the scientific logic that allogeneic stem cells extracted in large numbers from young and healthy donors could be physiologically, metabolically and genetically more stable. Therefore stem cells from young donors may be expected to exhibit higher vigor in secreting trophic factors leading to activation of host tissue-specific stem cells and also be more efficient in remodeling the micro-environmental niche of damaged tissue.

Matched MeSH terms: Regenerative Medicine/methods*
Fulltext Induced pluripotent stem cells in research and therapy

Teoh HK, Cheong SK

Malays J Pathol, 2012 Jun;34(1):1-13.
PMID: 22870592 MyJurnal

Induced pluripotent stem cells (iPSC) are derived from human somatic cells through ectopic expression of transcription factors. This landmark discovery has been considered as a major development towards patient-specific iPSC for various biomedical applications. Unlimited self renewal capacity, pluripotency and ease of accessibility to donor tissues contribute to the versatility of iPSC. The therapeutic potential of iPSC in regenerative medicine, cell-based therapy, disease modelling and drug discovery is indeed very promising. Continuous progress in iPSC technology provides clearer understanding of disease pathogenesis and ultimately new optimism in developing treatment or cure for human diseases.

Matched MeSH terms: Regenerative Medicine/methods*
Application of Ti3 C2 MXene Quantum Dots for Immunomodulation and Regenerative Medicine

Rafieerad A, Yan W, Sequiera GL, Sareen N, Abu-El-Rub E, Moudgil M, et al.

Adv Healthc Mater, 2019 08;8(16):e1900569.
PMID: 31265217 DOI: 10.1002/adhm.201900569

Inflammation is tightly linked to tissue injury. In regenerative medicine, immune activation plays a key role in rejection of transplanted stem cells and reduces the efficacy of stem cell therapies. Next-generation smart biomaterials are reported to possess multiple biologic properties for tissue repair. Here, the first use of 0D titanium carbide (Ti3 C2 ) MXene quantum dots (MQDs) for immunomodulation is presented with the goal of enhancing material-based tissue repair after injury. MQDs possess intrinsic immunomodulatory properties and selectively reduce activation of human CD4+ IFN-γ+ T-lymphocytes (control 87.1 ± 2.0%, MQDs 68.3 ± 5.4%) while promoting expansion of immunosuppressive CD4+ CD25+ FoxP3+ regulatory T-cells (control 5.5 ± 0.7%, MQDs 8.5 ± 0.8%) in a stimulated lymphocyte population. Furthermore, MQDs are biocompatible with bone marrow-derived mesenchymal stem cells and induced pluripotent stem cell-derived fibroblasts. Finally, Ti3 C2 MQDs are incorporated into a chitosan-based hydrogel to create a 3D platform with enhanced physicochemical properties for stem cell delivery and tissue repair. This composite hydrogel demonstrates increased conductivity while maintaining injectability and thermosensitivity. These findings suggest that this new class of biomaterials may help bridge the translational gap in material and stem cell-based therapies for tissue repair and treatment of inflammatory and degenerative diseases.

Matched MeSH terms: Regenerative Medicine/methods*

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