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Article: Cell and Cell-Free Therapies to Counteract Human Premature and Physiological Aging: MSCs Come to Light.

Infante, Arantza / Rodríguez, Clara I

2021 Volume 11, Issue 10

Abstract: The progressive loss of the regenerative potential of tissues is one of the most obvious consequences of aging, driven by altered intercellular communication, cell senescence and niche-specific stem cell exhaustion, among other drivers. Mesenchymal ... ...

Abstract	The progressive loss of the regenerative potential of tissues is one of the most obvious consequences of aging, driven by altered intercellular communication, cell senescence and niche-specific stem cell exhaustion, among other drivers. Mesenchymal tissues, such as bone, cartilage and fat, which originate from mesenchymal stem cell (MSC) differentiation, are especially affected by aging. Senescent MSCs show limited proliferative capacity and impairment in key defining features: their multipotent differentiation and secretory abilities, leading to diminished function and deleterious consequences for tissue homeostasis. In the past few years, several interventions to improve human healthspan by counteracting the cellular and molecular consequences of aging have moved closer to the clinic. Taking into account the MSC exhaustion occurring in aging, advanced therapies based on the potential use of young allogeneic MSCs and derivatives, such as extracellular vesicles (EVs), are gaining attention. Based on encouraging pre-clinical and clinical data, this review assesses the strong potential of MSC-based (cell and cell-free) therapies to counteract age-related consequences in both physiological and premature aging scenarios. We also discuss the mechanisms of action of these therapies and the possibility of enhancing their clinical potential by exposing MSCs to niche-relevant signals.
Language	English
Publishing date	2021-10-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662248-8
ISSN	2075-4426
ISSN	2075-4426
DOI	10.3390/jpm11101043
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Article: Circulating TGF-β Pathway in Osteogenesis Imperfecta Pediatric Patients Subjected to MSCs-Based Cell Therapy.

Infante, Arantza / Cabodevilla, Leire / Gener, Blanca / Rodríguez, Clara I

Frontiers in cell and developmental biology

2022 Volume 10, Page(s) 830928

Abstract: Osteogenesis Imperfecta (OI) is a rare genetic disease characterized by bone fragility, with a wide range in the severity of clinical manifestations. The majority of cases are due to mutations ... ...

Abstract	Osteogenesis Imperfecta (OI) is a rare genetic disease characterized by bone fragility, with a wide range in the severity of clinical manifestations. The majority of cases are due to mutations in
Language	English
Publishing date	2022-02-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2022.830928
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Article ; Online: Educating EVs to Improve Bone Regeneration: Getting Closer to the Clinic.

Infante, Arantza / Alcorta-Sevillano, Natividad / Macías, Iratxe / Rodríguez, Clara I

International journal of molecular sciences

2022 Volume 23, Issue 3

Abstract: The incidence of bone-related disorders is continuously growing as the aging of the population in developing countries continues to increase. Although therapeutic interventions for bone regeneration exist, their effectiveness is questioned, especially ... ...

Abstract	The incidence of bone-related disorders is continuously growing as the aging of the population in developing countries continues to increase. Although therapeutic interventions for bone regeneration exist, their effectiveness is questioned, especially under certain circumstances, such as critical size defects. This gap of curative options has led to the search for new and more effective therapeutic approaches for bone regeneration; among them, the possibility of using extracellular vesicles (EVs) is gaining ground. EVs are secreted, biocompatible, nano-sized vesicles that play a pivotal role as messengers between donor and target cells, mediated by their specific cargo. Evidence shows that bone-relevant cells secrete osteoanabolic EVs, whose functionality can be further improved by several strategies. This, together with the low immunogenicity of EVs and their storage advantages, make them attractive candidates for clinical prospects in bone regeneration. However, before EVs reach clinical translation, a number of concerns should be addressed. Unraveling the EVs' mode of action in bone regeneration is one of them; the molecular mediators driving their osteoanabolic effects in acceptor cells are now beginning to be uncovered. Increasing the functional and bone targeting abilities of EVs are also matters of intense research. Here, we summarize the cell sources offering osteoanabolic EVs, and the current knowledge about the molecular cargos that mediate bone regeneration. Moreover, we discuss strategies under development to improve the osteoanabolic and bone-targeting potential of EVs.
MeSH term(s)	Bone Regeneration ; Extracellular Vesicles/genetics ; Extracellular Vesicles/metabolism ; Humans ; MicroRNAs/genetics ; Translational Research, Biomedical
Chemical Substances	MicroRNAs
Language	English
Publishing date	2022-02-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23031865
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Article ; Online: Osteogenesis and aging: lessons from mesenchymal stem cells.

Infante, Arantza / Rodríguez, Clara I

Stem cell research & therapy

2018 Volume 9, Issue 1, Page(s) 244

Abstract: Aging is a high risk factor for the development of osteoporosis, a multifactorial age-related progressive disease characterized by reduced bone mass and increased risk of fractures. At the cellular level, the mesenchymal stem cell pool in the bone marrow ...

Abstract	Aging is a high risk factor for the development of osteoporosis, a multifactorial age-related progressive disease characterized by reduced bone mass and increased risk of fractures. At the cellular level, the mesenchymal stem cell pool in the bone marrow niche shows a biased differentiation into adipogenesis at the cost of osteogenesis. This differentiation shift leads to decreased bone formation, contributing to the etiology of osteoporosis. This review will focus on the most recent/relevant molecular findings driving this functional impairment of mesenchymal stem cells in the aging process.
MeSH term(s)	Adipogenesis/genetics ; Aging/genetics ; Aging/pathology ; Bone Marrow Cells/pathology ; Cell Differentiation/genetics ; Humans ; Mesenchymal Stem Cells/cytology ; Osteogenesis/genetics ; Stem Cell Niche/genetics
Language	English
Publishing date	2018-09-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-018-0995-x
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Article ; Online: Secretome analysis of in vitro aged human mesenchymal stem cells reveals IGFBP7 as a putative factor for promoting osteogenesis.

Infante, Arantza / Rodríguez, Clara I

Scientific reports

2018 Volume 8, Issue 1, Page(s) 4632

Abstract: Aging is a complex biological process, which involves multiple mechanisms with different levels of regulation. Senescent cells are known to secrete senescence-associated proteins, which exert negative influences on surrounding cells. Mesenchymal stem ... ...

Abstract	Aging is a complex biological process, which involves multiple mechanisms with different levels of regulation. Senescent cells are known to secrete senescence-associated proteins, which exert negative influences on surrounding cells. Mesenchymal stem cells (MSCs), the common progenitors for bone, cartilage and adipose tissue (which are especially affected tissues in aging), are known to secrete a broad spectrum of biologically active proteins with both paracrine and autocrine functions in many biological processes. In this report, we have studied the secreted factors (secretome) from human MSCs (hMSCs) and hMSCs-derived adipocytes which were induced to accumulate prelamin A, the immature form of the nuclear lamina protein called Lamin A, known to induce premature aging syndromes in humans and in murine models. Proteomic analysis from two different techniques, antibody arrays and LS-MS, showed that prelamin A accumulation in hMSCs promotes the differential secretion of factors previously identified as secreted by hMSCs undergoing osteogenesis. Moreover, this secretome was able to modulate osteogenesis of normal hMSCs in vitro. Finally, we found that one of the overexpressed secreted factors of this human aging in vitro stem cell model, IGFBP-7, is an osteogenic factor, essential for the viability of hMSCs during osteogenesis.
MeSH term(s)	Adipose Tissue/cytology ; Adipose Tissue/metabolism ; Cells, Cultured ; Cellular Senescence ; Humans ; Insulin-Like Growth Factor Binding Proteins/metabolism ; Lamin Type A/metabolism ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Osteogenesis ; Proteome/analysis
Chemical Substances	Insulin-Like Growth Factor Binding Proteins ; Lamin Type A ; Proteome ; insulin-like growth factor binding protein-related protein 1 ; prelamin A
Language	English
Publishing date	2018-03-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-22855-z
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Article ; Online: Cutting Edge Endogenous Promoting and Exogenous Driven Strategies for Bone Regeneration.

Macías, Iratxe / Alcorta-Sevillano, Natividad / Infante, Arantza / Rodríguez, Clara I

International journal of molecular sciences

2021 Volume 22, Issue 14

Abstract: Bone damage leading to bone loss can arise from a wide range of causes, including those intrinsic to individuals such as infections or diseases with metabolic (diabetes), genetic (osteogenesis imperfecta), and/or age-related (osteoporosis) etiology, or ... ...

Abstract	Bone damage leading to bone loss can arise from a wide range of causes, including those intrinsic to individuals such as infections or diseases with metabolic (diabetes), genetic (osteogenesis imperfecta), and/or age-related (osteoporosis) etiology, or extrinsic ones coming from external insults such as trauma or surgery. Although bone tissue has an intrinsic capacity of self-repair, large bone defects often require anabolic treatments targeting bone formation process and/or bone grafts, aiming to restore bone loss. The current bone surrogates used for clinical purposes are autologous, allogeneic, or xenogeneic bone grafts, which although effective imply a number of limitations: the need to remove bone from another location in the case of autologous transplants and the possibility of an immune rejection when using allogeneic or xenogeneic grafts. To overcome these limitations, cutting edge therapies for skeletal regeneration of bone defects are currently under extensive research with promising results; such as those boosting endogenous bone regeneration, by the stimulation of host cells, or the ones driven exogenously with scaffolds, biomolecules, and mesenchymal stem cells as key players of bone healing process.
MeSH term(s)	Animals ; Bone Regeneration/physiology ; Bone and Bones/physiology ; Graft Rejection/physiopathology ; Humans ; Mesenchymal Stem Cells/physiology ; Osteogenesis/physiology ; Tissue Scaffolds/chemistry ; Wound Healing/physiology
Language	English
Publishing date	2021-07-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22147724
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Article ; Online: Immunomodulatory Effects of MSCs in Bone Healing.

Medhat, Dalia / Rodríguez, Clara I / Infante, Arantza

International journal of molecular sciences

2019 Volume 20, Issue 21

Abstract: Mesenchymal stem cells (MSCs) are capable of differentiating into multilineage cells, thus making them a significant prospect as a cell source for regenerative therapy; however, the differentiation capacity of MSCs into osteoblasts seems to not be the ... ...

Abstract	Mesenchymal stem cells (MSCs) are capable of differentiating into multilineage cells, thus making them a significant prospect as a cell source for regenerative therapy; however, the differentiation capacity of MSCs into osteoblasts seems to not be the main mechanism responsible for the benefits associated with human mesenchymal stem cells hMSCs when used in cell therapy approaches. The process of bone fracture restoration starts with an instant inflammatory reaction, as the innate immune system responds with cytokines that enhance and activate many cell types, including MSCs, at the site of the injury. In this review, we address the influence of MSCs on the immune system in fracture repair and osteogenesis. This paradigm offers a means of distinguishing target bone diseases to be treated with MSC therapy to enhance bone repair by targeting the crosstalk between MSCs and the immune system.
MeSH term(s)	Animals ; Cell Differentiation/immunology ; Cytokines/immunology ; Cytokines/metabolism ; Cytokines/pharmacology ; Fractures, Bone/immunology ; Fractures, Bone/physiopathology ; Fractures, Bone/therapy ; Humans ; Immunomodulation/drug effects ; Immunomodulation/immunology ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/immunology ; Osteoblasts/immunology ; Osteogenesis/drug effects ; Osteogenesis/immunology ; Regenerative Medicine/methods ; Regenerative Medicine/trends
Chemical Substances	Cytokines
Language	English
Publishing date	2019-11-02
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20215467
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Article ; Online: Crucial Role of Lamin A/C in the Migration and Differentiation of MSCs in Bone.

Alcorta-Sevillano, Natividad / Macías, Iratxe / Rodríguez, Clara I / Infante, Arantza

Cells

2020 Volume 9, Issue 6

Abstract: Lamin A/C, intermediate filament proteins from the nuclear lamina encoded by ... ...

Abstract	Lamin A/C, intermediate filament proteins from the nuclear lamina encoded by the
MeSH term(s)	Animals ; Bone and Bones/cytology ; Cell Differentiation ; Cell Movement ; Humans ; Lamin Type A/metabolism ; Mesenchymal Stem Cells/cytology ; Osteogenesis
Chemical Substances	Lamin Type A
Language	English
Publishing date	2020-05-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9061330
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Article ; Online: Osteoporosis and the Potential of Cell-Based Therapeutic Strategies.

Macías, Iratxe / Alcorta-Sevillano, Natividad / Rodríguez, Clara I / Infante, Arantza

International journal of molecular sciences

2020 Volume 21, Issue 5

Abstract: Osteoporosis, the most common chronic metabolic bone disease, is characterized by low bone mass and increased bone fragility. Nowadays more than 200 million individuals are suffering from osteoporosis and still the number of affected people is ... ...

Abstract	Osteoporosis, the most common chronic metabolic bone disease, is characterized by low bone mass and increased bone fragility. Nowadays more than 200 million individuals are suffering from osteoporosis and still the number of affected people is dramatically increasing due to an aging population and longer life, representing a major public health problem. Current osteoporosis treatments are mainly designed to decrease bone resorption, presenting serious adverse effects that limit their safety for long-term use. Numerous studies with mesenchymal stem cells (MSCs) have helped to increase the knowledge regarding the mechanisms that underlie the progression of osteoporosis. Emerging clinical and molecular evidence suggests that inflammation exerts a significant influence on bone turnover, thereby on osteoporosis. In this regard, MSCs have proven to possess broad immunoregulatory capabilities, modulating both adaptive and innate immunity. Here, we will discuss the role that MSCs play in the etiopathology of osteoporosis and their potential use for the treatment of this disease.
MeSH term(s)	Biomarkers/metabolism ; Bone Remodeling ; Humans ; Inflammation/pathology ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology ; Osteoporosis/pathology ; Osteoporosis/physiopathology ; Osteoporosis/therapy
Chemical Substances	Biomarkers
Language	English
Publishing date	2020-02-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21051653
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Article ; Online: Deciphering the Relevance of Bone ECM Signaling.

Alcorta-Sevillano, Natividad / Macías, Iratxe / Infante, Arantza / Rodríguez, Clara I

Cells

2020 Volume 9, Issue 12

Abstract: Bone mineral density, a bone matrix parameter frequently used to predict fracture risk, is not the only one to affect bone fragility. Other factors, including the extracellular matrix (ECM) composition and microarchitecture, are of paramount relevance in ...

Abstract	Bone mineral density, a bone matrix parameter frequently used to predict fracture risk, is not the only one to affect bone fragility. Other factors, including the extracellular matrix (ECM) composition and microarchitecture, are of paramount relevance in this process. The bone ECM is a noncellular three-dimensional structure secreted by cells into the extracellular space, which comprises inorganic and organic compounds. The main inorganic components of the ECM are calcium-deficient apatite and trace elements, while the organic ECM consists of collagen type I and noncollagenous proteins. Bone ECM dynamically interacts with osteoblasts and osteoclasts to regulate the formation of new bone during regeneration. Thus, the composition and structure of inorganic and organic bone matrix may directly affect bone quality. Moreover, proteins that compose ECM, beyond their structural role have other crucial biological functions, thanks to their ability to bind multiple interacting partners like other ECM proteins, growth factors, signal receptors and adhesion molecules. Thus, ECM proteins provide a complex network of biochemical and physiological signals. Herein, we summarize different ECM factors that are essential to bone strength besides, discussing how these parameters are altered in pathological conditions related with bone fragility.
MeSH term(s)	Animals ; Bone Density ; Bone Matrix/metabolism ; Bone and Bones/metabolism ; Collagen/chemistry ; Extracellular Matrix/metabolism ; Extracellular Matrix Proteins/metabolism ; Fractures, Bone/metabolism ; Homeostasis ; Humans ; Integrins/metabolism ; Matrix Metalloproteinases/metabolism ; Osteoblasts/metabolism ; Osteoclasts/metabolism ; Osteogenesis Imperfecta/metabolism ; Osteoporosis/metabolism ; Signal Transduction ; Transforming Growth Factor beta/metabolism ; Wnt Proteins/metabolism
Chemical Substances	Extracellular Matrix Proteins ; Integrins ; Transforming Growth Factor beta ; Wnt Proteins ; Collagen (9007-34-5) ; Matrix Metalloproteinases (EC 3.4.24.-)
Language	English
Publishing date	2020-12-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9122630
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