An insight on Mesenchymal stem cells: A review

Introduction

STEM cells classification

According to their origin, stem cells have been categorized as "adult stem cells (ASCs)" or "embryonic stem cells (ESCs)". Ectoderm, endoderm, and mesoderm are 3 germ layers from which ESCs can differentiate into several cell types due to their pluripotency. On contrary, ASCs, which are isolated from adult tissues, have multipotent to unipotent properties.

STEM cells biology

Adult stem cells, particularly "mesenchymal stem cells (MSCs)", are distributed as viable substitute for pluripotent stem cells due to their pluripotent characteristics, which are linked to concerns of immune rejection as well as teratoma formation. Since MSCs are pluripotent, they can transdifferentiate into ectoderm and endoderm in addition to mesoderm (Ullah, 2015) [25] . "Embryonic stem cells (ESCs) are derived from inner cell mass of blastocyst, a preimplantation embryonic stage that happens about four days after fertilization. These cells are then placed in a culture dish that has culture media" in it. A common but ineffective technique for subculturing cells to various dishes is passage. Smaller cell clusters are produced on a new culture surface by cell passaging. Ability of these cells to differentiate into any type of cell within body is what makes them pluripotent. Somatic stem cells have a longer proliferative period than ESCs. Reprogramming adult stem cells to become pluripotent is possible. The adult nucleus can be fused with a pluripotent cell or introduced into the cytoplasm of oocyte for accomplishing this. The cloning of famous "Dolly sheep" was done using the same procedure. The signals that affect process of stem cell specialization is divided into two categories: internal factors, which are controlled by genetic information in DNA, and external factors, which include chemical secretions from nearby tissues or cellular interaction. Growth hormones and nutrients are necessary for the differentiation and development of stem cells. Medium must be replaced every day. If stem cells are not differentiated into appropriate cell types for therapy, the entire regenerative medicine procedure will be ineffective.

Undifferentiated ESCs have potential to develop into teratomas in vivo, hence, differentiation is crucial. For regenerative medicine to be effective, it's essential to understand and use signalling pathways for differentiation. Directed differentiation most likely mimics signals that cells acquire as they progress through developing phases (Oh Y, 2019). However, it is challenging to achieve a similar effect in vivo. Several variables can be impacted by a signalling molecule's concentration levels and duration of action. A stem cell as well as differentiated cell can be distinguished from one another by their DNA. DNA is loosely arranged with functioning genes in former cell. Unnecessary genes are deactivated as signals enter cell and differentiation process commences, but genes necessary for specific function remain active. It is known that interactions within gene sequences can achieve pluripotency, and this process is reversible.

MSCS and related vascular cell types

"MSCs are spindle-shaped, plastic-adherent cells that can be isolated from adult organs, like bone marrow and various other body tissues", as well as from foetus and extraembryonic tissues. Friedenstein et al., (1970) [6] first described MSCs as hematopoietic-supporting cells found in bone marrow stroma. These cells can differentiate into multiple mesenchymal tissue lineages, encompassing bone, tendon, cartilage, marrow stroma, ligament, adipocytes, muscle, dermis, and connective tissue, hence, Owen and Friedenstein (1988) [16] suggested that these cells be referred to as MSCs. Although they come from tissue, are they authentic stem cells in vivo? Although MSCs are frequently employed in tissue engineering as well as regenerative medicine, some studies have linked them to previously identified histological cells in bone marrow, including reticulocytes, stromal cells, or fibroblasts. However, since MSCs are so rare, this is unlikely to be the case, and it is still unknown what MSCs appear like in vivo. Moreover, whereas bone marrow was initially utilized for isolation of MSCs and regarded as "renewable source, MSC-like cells have been extracted from several tissue sources, encompassing retrieved adipose tissue, umbilical Wharton's jelly, placenta, skin, and roots of shed teeth. Phenotypic similarities among investigations of microvascular pericytes and attempts to assess inherent identity of in vivo MSCs were observed by Caplan (2017) [2] . Crisan et al. (2012) [4] demonstrated that pericytes isolated via flow cytometry from various human organs and cultured through multiple passages are indistinguishable from traditional, bone marrow-derived MSCs regarding morphology, surface antigen expression, proliferation kinetics, and differentiation potential, both in vitro and in vivo".

Pericytes as MSC innate forerunners

The perivascular areas surrounding larger arteries and veins were then included in this paradigm, where group of fibroblast-like putative MSCs is found in the outermost tunica adventitia.79 MSCs can respond rapidly to tissue damage because of their interaction with the vasculature.

Whether perivascular cells serve "same progenitor function in their in vivo environment is a major unresolved issue surrounding the possible identification of these cells as innate MSC progenitors. Up to one-third of all expressed genes showed significant up regulation or down regulation, indicating significant differences in gene expression between their development in culture and transition to in vitro MSC phenotype."

Properties of MSCS and pericytes

After bone marrow-derived MSCs inhibit T-cells, MSCs can affect inflammatory and immunological responses (Jiang and Xu, 2020) [11] . Additionally, MSCs produce many secretomes and proteomes and secrete several cytokines, growth factors, and chemokines that improve metabolism. These compounds have a major impact on immunomodulatory functions, promoting the differentiation of MSCs, HSC engraftment, and control of angiogenesis and apoptosis (Wu et al, 2020) [29] . Utilizing MSCs' capability of producing cytokines in addition to factors that support innate tissue healing and control inflammation along with immunological responses has become the main emphasis in the past ten years.

MSCS as novel therapy

MSCs have the potential to be a unique treatment method for several disorders because of their incredible capacities for immune regulation and multipotential differentiation (Hoang et al, 2022) [9] . MSCs have also been used in therapeutic studies for myocardial infarction, multiple sclerosis, and type 1 diabetes mellitus (Moreira et al, 2017) [14] . According to research, soluble substances produced by MSCs improve the effectiveness of treatments for autoimmune disorders, which is of great importance. Inflammatory conditions have been the focus of recent research on MSCs' immune-regulatory capabilities (Zaripova et al, 2023) [30] .

The transition from "cell replacement to altering body's cellular and tissue responses through clinical perspective represents progress in understanding accessible ex vivo expanded MSCs". MSCs' immune modulation as well as anti-inflammatory applications are significantly relevant in damaged tissue.

MSCS for organ transplantation

MSCs are immunoprivileged. Capability of MSCs to avoid negative immune system reactions among people allows them to be transplanted into a variety of persons without the possibility of rejection. These transplants have potent immunosuppressive and anti-inflammatory properties and greatly improve the body's natural healing abilities.

MSCS for regenerative medicine

"MSCs have a considerable capacity for self-renewal while preserving multipotency, similar to other types of stem cells". As a result, MSCs offer substantial therapeutic promise for tissue repair. Numerous cell types, encompassing chondrocytes, osteocytes, adipocytes, and cardiomyocytes, can be differentiated from MSCs. Understanding and applying signaling pathways for differentiation is essential approach for successful regenerative therapies. Directed differentiation most probably mimics signals that cells acquire as they progress through developmental phases (Cohen & Melton, 2011) [3] .

MSCS as inflammatory regulators

Natural killer (NK) cells, B cells, T cells, neutrophils, dendritic cells (DCs), as well as macrophages are among the inflammatory regulator cell types that MSCs can interact with (Wang et al, 2018) [27] . MSCs have been demonstrated to possess anti-inflammatory properties by secreting several cytokines and chemokines that suppress immunological responses mediated by T cells (Ren et al, 2008) [18] . Inflammation can be reduced and tissue healing accelerated by M2 macrophages. MSCs decrease inflammatory cytokine levels while increasing phagocytic activity and IL-10 release by inducing the production of M2 macrophages.

Regenerative along with anti-inflammatory properties of MSCs have made them useful therapeutic agents for a variety of conditions, particularly immunological and bone disorders.

MSCS in autoimmune diseases

Significant amounts of immunosuppressive agents, chemokines, and adhesion molecules are released by mesenchymal stem cells (MSCs) that assist in efficient suppression of T cells, promote T cell proliferation and death, and affect differentiation (Wang et al, 2008) [27] . By blocking the generation of tumor necrosis factor (TNF), MSCs may reduce the proinflammatory potential of DCs. DCs are immunosuppressed by MSCs because they prevent DCs from developing from monocytes and decrease expression of cell-surface markers CD1-α, CD40, CD80, CD83, CD86, as well as MHCII (Tze et al, 2011) [23] . After incubating with MSCs, DCs tend to elevate IL-10 release while down regulating the production of TNF-α as well as interferon-γ (IFN-γ) to reduce their capacity to stimulate lymphocytes (Wang, 2022) [28] . In order to induce MSCmediated immunosuppression, mechanisms of interaction depend upon cell-cell contact and the synthesis of soluble immune molecules (Song et al, 2020) [22] .

MSCS as a target for pharmacological drug testing

Stem cells could be applied to novel pharmacological evaluations. Pluripotent cells can be employed to develop specialized differentiated cells that can be used safely in living tissue experiments. Drug formulations may be modified until they achieve optimal level of efficacy if any negative side effects develop. It is possible to introduce a drug into the pharmaceutical market without endangering any living being. Comparing the effects of the two drugs requires standardizing the conditions in order to evaluate them accurately.

Conclusion

Application of stem cells for treatment is becoming a major therapeutic revolution after many decades of research.

Although there are numerous challenges to overcome, the potential of stem cells is growing with each experiment. In both transplantation and regenerative medicine, stem cells have a significant impact. With a thorough understanding of complex biology along with therapeutic potential of MSCs, substantial advances in scientific understanding and clinical advantages are expected.

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