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Current IssueSpecial IssueEditorial BoardOnline First ArticlesArchive

Review Article

Mesenchymal Stem Cells-Their Immunomodulatory Potential and Clinical Applications in Veterinary Medicine: A Review

Z
Zahoor A. Pampori1,*
A
Aasif A. Sheikh1
1Division of Veterinary Physiology, Faculty of Veterinary Sciences and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology-Kashmir, Srinagar-190006, Jammu and Kashmir, India.

ABSTRACT

Livestock is a crucial component of global animal husbandry that plays a vital role in sustaining human life and supporting the social and economic development. The application of stem cell technologies in livestock has demonstrated great potential to enhance productivity, improve animal welfare and support the sustainable development of animal husbandry practices. Among the stem cells, mesenchymal stem cells (MSCs) are one of the most promising cell populations owing to their multiple differentiation potential, homing property and immunomodulatory properties. This feature of plasticity makes MSCs favourable candidates for use in veterinary medicine. MSC therapy has potential in enhancing reproductive efficiency, improving overall production performance, addressing common injuries affecting bones, muscle and skin tissues through tissue specific differentiation, immunomodulation, secretion of diverse bioactive molecules and antimicrobial proteins. MSCs have been successfully used in tissue repair, wound healing, fractures, inflammation, mastitis, tissue grafts and organ transplants in livestock and companion animals. MSCs have recently been engineered and used as drug carriers to treat various tumours. The diverse properties of MSCs have evolved hope to combat antimicrobial resistance and treatment of diseases considered untreatable thus ensuring sustainable, organic, safe and nutritious food of animal origin. Of the utmost importance to MSC research is the identification of MSC sources that are easily obtainable, ethically acceptable, economically viable and stable. The livestock birth by-products such as umbilical cord, Wharton’s jelly, amniotic sac and amniotic fluid have been proposed as ideal sources of multiple stem cell lineages. The use of foetal adnexal tissue for isolation of MSCs has many potential advantages like the non-invasive nature of isolation, large tissue mass and ethical acceptance. In vitro expansion and differentiation potential of MSCs make these birth by-products as an attractive source of MSCs for regenerative therapies and biotechnological applications.

INTRODUCTION

In vitro cell culture technology has advanced significantly over last few decades and has attained robustness, reliability and maturity in its being used as a technology (Li et al., 2010). In-vitro cell culture has provided a commercial setup for production of therapeutic proteins or biomolecules. Cell culture technology has made advances and has become a key modelling system for large class of biotechnological interventions, clinical and industrial applications. Evans and Kaufman (1981) establishing a platform for pluripotent stem cells while harvesting mouse embryonic stem cells from mouse embryos. Stem cell culture has revolutionized the therapeutics and provided remedies to the diseases that were known to be untreated. Stem cell culture has also provided potential solution to regenerate the damaged tissue through paracrine secretions and/ or through the trans-differentiation or through integration and fusion with the native host cells (Xu et al., 2010). Stem cell therapy is gaining momentum to address various ailments that were earlier considered untreatable and its applicability has also spread tremendously through creation of stem cell banks, to safeguard new-borns against the impact of medical conditions. There are number of sources of stem cells either in adults or in foetuses or foetal appendages that are cultured in-vitro and directed to differentiate into desired type of cells for a particular treatment regime.

Differentiation potential of cells
 
In mammalian species, the union of male and female gametes at fertilization results into the formation of zygote/one cell embryo. The zygote or early cleavage stage blastomeres up to 4 cell stage has the potency to develop in a predictable manner into a complete species-specific adult organism, hence termed as totipotent cells (Aggarwal and Pittenger, 2005). The restriction in the potency occurs gradually as development proceeds. The cells of the late morula/early blastocyst/ inner cell mass (ICM) are pluripotent that are able to produce all or most of the cells of the body or all the derivatives of the three primary germ layers, however, are not capable of organizing and integrating them into a coherent adult body/organism. The germ-layer cells are much less plastic, referred as multipotent stem cells present in almost all the body tissues, that can give rise to limited number of cell types preferably of the same germ layer from which the stem cells are derived e.g. mesenchymal stem cells, haematopoietic stem cells (Krampera et al., 2007). As the embryo advances in its organization, the differentiation potential of cells gets restricted and the non-plastic version of cells, known as unipotent cells or somatic cells capable of dividing and giving rise to only its own cell type, are established (Pampori et al., 2024).
       
Stem cells are non-specialized, undifferentiated cells having self-renewal capacity, excessive production and capability to differentiate into several types of highly specialized cells in the body (Fathi and Farahzadi, 2016). Friedenstein et al., (1970) cultured the bone marrow cells from rats and found them morphologically similar to fibroblasts, exhibiting plastic adherence. Three major types of stem cells that have been described are (i) Embryonic Stem Cells (ii) Adult Stem Cells and (iii) Induced Pluripotent Stem Cells (Table 1). Embryonic stem cells (ESC) are obtained from the inner cell mass of the blastocyst and are associated with tumorigenesis and ethical issues. The adult stem cells isolated from any adult tissue have invasive nature and are ethically unacceptable. Induced pluripotent stem cells (iPSC) can be obtained by inducing dedifferentiation of adult somatic cells through a recently developed in vitro technology known as cell reprogramming (Takahashi et al., 2007).

Table 1: Types of stem cells and their characteristics.


       
Besides the two common sources, the embryonic and the adult stem cells, extra-embryonic tissues (amnion, placenta and umbilical cord matrix) have been found as potential source of stem cells (Zhang et al., 2006). While evidence suggests that mesenchymal stem cells (MSCs) are present in almost all the tissues, they were first isolated from murine bone marrow by Friedenstein et al. (1966) and were termed as hematopoiesis-supporting cells in bone marrow. MSCs have been isolated from a variety of tissues such as bone marrow (Friedenstein et al., 1987), adipose tissue (Yang et al., 2010), birth-derived tissues (Gang et al., 2004), peripheral blood (Tondreau et al., 2005), Skin (Toma et al., 2005), muscle (Jackson et al., 2010), ovarian surface epithelium (Ajeet et al., 2022) etc.  (Fig 1). MSCs have been isolated and expanded in animal species like equines, canines, bovines, caprines and ovines. MSCs have been harvested successfully from equine bone marrow (Smith et al., 2003), adipose tissue (Vidal et al., 2008), peripheral blood (Giovannini et al., 2008) and umbilical cord blood (Reed et al., 2008). MSCs have been successfully harvested from cord blood by Raoufi et al., (2011) in bovine, by Shah et al., (2023) in ovines and by Ajeet et al., (2022) in canines. MSCs have been isolated and expanded in vitro from umbilical cord blood, amniotic fluid, Wharton’s jelly and amniotic membrane in sheep (Shah et al., 2023). MSCs were isolated from ovine foetal adnexa differentiated into three lineages viz. chondrogenic, osteogenic and adipogenic using differential media and retained the stemness after cryopreservation, thus opening a new window of cryopreservation of MSCs for future application in medicine (Khan, 2023 and Safia, 2023).

Fig 1: Different sources of MSCs and their differentiation potential.


 
Characteristics of mesenchymal stem cells
 
Mesenchymal stem cells (MSCs) are stromal cells having the ability to self-renew, with multipotency, accessibility and immunomodulatory attributes. They can expand ex vivo in culture and differentiate into osteogenic, chondrogenic, adipogenic, myogenic cells and other lineages (Wei et al., 2013). MSCs are plastic adherent with typical spindle morphology, form clusters, besides express CD73, CD90 and CD105 and lack CD45, CD34, CD19, CD14 and CD3 the most important hematopoietic markers (Baghaei et al., 2017). Ruan et al., (2022) reported the homing property of MSCs and traced their migration, colonization and survival in Tree Shrew. Besides getting differentiated into various cell types, MSCs are reported to have immuno-modulatory competence which is predominantly exerted by a synergy of cell contact-dependent processes and soluble factors (Gnecchi et al., 2016). MSCs unlike ESCs and iPSCs have minimal teratogenicity, ethical issues and immune rejection.  They often lack major histocompatibility complex (MHC-II), prevent T-cell responses via the modulation of dendritic cells and disruption of natural killer (NK) cells that makes MSCs preferred therapeutic candidates (Spaggiari et al., 2008). MSCs in converse to Embryonic stem cells (ESCs) have restricted culture lifespan and after certain culture passages these cells become senescent (Caplan, 2017). Even upon in vivo implantation, MSCs (autologous/allogeneic) survive only for certain period (ranging from few hours to as long as 90 days) but not for an indefinite period (Eggenhofer et al., 2012).
 
Non-expensive, non-invasive and attractive source of mesenchymal stem cells
 
Owing to the unique characteristics of MSCs and their application in regenerative medicine, the research in obtaining these cells in large numbers in an inexpensive and non-invasive way without any risk to the donor has been identified in gestational or foetal adnexal tissues like foetal membranes, foetal fluid, umbilical cord matrix and cord blood. Stem cells obtained from these commonly referred “biohazardous afterbirth waste” are attractive candidates of MSCs. The adnexal tissue cells preserve some of the characteristics of the primitive embryonic layers from which they originate. The feasibility to collect large numbers of cells in an inexpensive, non-invasive way and the ability to cryogenically bank and expand the cells in vitro are important considerations to harvest the MSCs from foetal adnexa for use in regenerative medicine. The ease of harvest and the quantity obtained make these sources most practical for experimental and possible clinical applications. There are likely more sources of MSCs waiting to be discovered that may prove good candidates for future experimental or clinical applications.
       
MSCs isolated from foetal adnexa have been reported to express specific pluripotent and MSC markers. Wharton’s Jelly or umbilical cord matrix-derived stem cells are present in relatively high numbers as compared to routinely isolated from adult bone marrow. Carlin et al., (2006) and Shah et al., (2023) emphasized that Wharton’s jelly is an easy and inexpensive source of stem cells based on the expression of transcription factors of pluripotency, adherence to plastic growth plates, colony-forming ability and in vitro expansion.
 
Therapeutic potential of mesenchymal stem cells
 
Stem cell culture has revolutionized the therapeutics and provided remedies to the diseases that were known to be untreated. Stem cell culture has also provided potential solution to regenerate the damaged tissue through paracrine activities and/or through the trans-differentiation or through integration and fusion with the native host cells (Pampori et al., 2024). Mesenchymal stem cells (MSCs) are considered the most promising cell populations for regenerative medicine and tissue engineering as the cells carry all in one therapeutic solution for diverse clinical disorders attributable to their characteristic properties such as self-renewal, multiplication, immune-modulation and multi-lineage differentiation potential (Gugjoo et al., 2017). However, lack of regulatory set up in India makes MSCs therapeutic applications in veterinary medicine a more complicated field (Gugjoo et al., 2022).
       
Non-embryonic extra-foetal derived stem cells have opened new perspectives for developmental biology and for regenerative medicine and have demonstrated variable differentiation potential based upon their tissue sources. Safia (2023) reported a source bias in the trilineage differentiation of ovine MSCs, cells from amniotic fluid exhibited highest adipogenic potential whereas MSCs from cord blood outperformed in chondrogenic and osteogenic potential determined as relative transcript abundance of lineage specific markers in the in vitro expanded MSCs which enables choice-based use of MSCs in regenerative medicine. Khan (2023) successfully cryopreserved the in vitro expanded ovine MSCs derived from foetal adnexa in liquid nitrogen and reported normal growth and stem cell marker expression post-thaw indicating that MSCs could be exploited for stem cell banking and future use in regenerative medicine.
 
Clinical application of mesenchymal stem cells in veterinary medicine
 
Presently, stem cell technology is being considered to carry potential to effectuate tissue regeneration through paracrine activities and/or through trans-differentiation (Xu et al., 2010). Foubert et al. (2017) reported that MSCs are normally present in the skin and are actively involved in its natural regeneration. They prevent hypertrophic scarring seen in chronic wounds and recurrent teat injuries through production of anti-fibrotic factors in porcine model. Stem cells have revealed significant promise in regenerating orthopaedic tissues in livestock such as cartilage (chondrogenesis), tendons and bones. This makes them a viable treatment option for conditions like osteoarthritis and mandible defects. Richardson et al., (2007) used MSCs derived from bone marrow and adipose tissue in treatment of strain-induced tendon injury in the horse and the outcome was encouraging as compared to the present therapeutic approaches. Carlier et al., (2024) used tenogenic primed MSCs intralesionally in sport horses having superficial digital flexor tendon and suspensory ligament injuries and reported safe and improved quality of healing and long-term outcomes, thus MSC therapy in high value racehorses can be a viable option to treat them. Yaşar and Perk (2023) reported significant improvement in osteoarthritis in dogs treated with MSCs which can replace the use of steroid and NSAID in such conditions. Jammes et al. (2023) reported that exosomes from MSCs primed with proinflammatory cytokines were promising therapy in treating osteoarthritis in equines. In goats Yu et al., (2021) employed bone mesenchymal stem cells on a scaffold in temporomandibular joint condyle defects and demonstratied efficiency of MSCs in correction of condyle defects. MSCs in veterinary medicine have been used to treat cartilage injury of dogs and horses (Ganiev et al., 2021). Bhat et al., (2019) revealed that MSCs can be safely used allogenically for spinal cord injury where the conventional medication is not promising and treated 44 clinical cases of spinal cord injury dogs with encouraging results. Bhatt et al., (2021) reported encouraging results in full thickness wound healing in Guinea pigs treated with MSCs. Gugjoo et al., (2020) reported that combined use of MSCs and growth factors could accelerate osteochondral healing in rabbits.
       
Pokorska et al., (2024) and Peralta et al., (2020) demonstrated that the MSCs administered either intravenous cum intramammary or intramammary only reduced the bacterial growth as well as somatic cell count in milk samples and were effective in reducing bovine mastitis without use of antibiotics. Harman et al., (2017) demonstrated that equine MSC inhibit bacterial growth through production of antimicrobial proteins in treatment of wounds in equines and human. Cahuascanco et al., (2019) reported that conditioned media from foetal bovine bone marrow and adipose tissue derived MSC has the capacity to reduce in average ~30% of S. aureus growth under in vitro conditions and can be a promising source of treating mastitis replacing antibiotics. Del Prete et al. (2024) demonstrated an overall positive effect of MSCs therapies in treating endometritis in equines through anti-inflammatory effect, reduced intrauterine fluid accumulation and cytokine concentrations with improvements in pregnancy, foaling and embryo recovery rates. Meissner et al., (2024) demonstrated that MSCs-derived extra cellular vesicles represent an innovative and promising therapeutic approach in treatment of corneal ulcers in horses.
       
Despite the pronounced advances over the past few decades in medicine, organ transplant technique still faces significant obstacles. MSCs from autologous and allogeneic sources are being used in transplant recipients to reduce the use of immunosuppressive drugs and thereby protect against graft rejection. Mesenchymal stem cells have a specific impact on the characteristics of transplantation and regenerative medicine thus emerging as a powerful tool in regenerative medical field.
 
Immune-modulatory functions of mesenchymal stem cells
 
MSCs participate in both innate and adaptive immunity and their immunomodulatory functions are exerted mainly via direct contact with immune cells (cell-to-cell contact) and through local micro-environmental factors (paracrine activity). MSCs are reported to cause modulation in lymphocyte proliferation, regulation of B-cell proliferation and function, induction of regulatory T-cell proliferation, inhibition of dendritic cell and natural killer cell activation (Spaggiari et al., 2006). MSCs inhibit T-cell proliferation induced by mitogens, CD3 and CD28 antibodies as well as allogeneic antigens (Devine et al., 2003). Co-culture of peripheral blood mononuclear cells (PBMCs) with MSCs causes shift from allogenic T-cell responses to the secretion of a Th2 cytokine profile and inhibition of cytotoxic lysis of allogeneic cells through induction of CCL1 and sHLA-G. MSCs have been shown to modulate immune responses by the de novo induction and expansion of CD4+, CD25+, FoxP3+ and CD8+ regulatory T-cells (Tregs) which are responsible for inhibiting allogeneic lymphocyte proliferation (Maccario et al., 2005). 
       
MSCs possess the capacity to block the proliferation of activated B-cells in the presence of IFN-γ and negatively interfere with antibody production (Bernardo et al., 2009). MSCs inhibit IL-2-induced NK cell proliferation which is primarily mediated by the soluble immunosuppressive factors TGF-β, sHLA-G and PGE-2 as well as cell-cell contact (Shi et al., 2011). MSCs also prevent NK cell effector functions like cytotoxicity against virus-infected cells through reduced IFN-γ secretion. MSCs interact with NK cells and influence the cytokine production through secretion of IDO (Indoleamine-2,3-Dioxygenase) and PGE-2 (Spaggiari et al., 2008). MSCs have been reported to down-regulate the expression of CD40, CD80, CD83 and CD86 on dendritic cells that interfere with their differentiation from CD14+ monocytes and CD34+ progenitor cells. Dendritic cells produced in the presence of MSCs secrete low levels of IL-12 and TNF-α, but high levels of IL-1β and IL-10, besides low expression levels of MHC class-II surface antigen indicating that antigen processing and presentation via MHC class-II surface antigens is impaired (Nauta et al., 2006).
       
Several studies have ascertained that the immunomodulatory effects of MSCs are mainly linked to MSC-secreted cytokines. The expression of TLR3 and TLR4 in MSCs has been shown to restore an efficient T-cell response to infection (Liotta et al., 2008). MSCs also affect B-cells through cell-to-cell contact and have shown to increase the survival of quiescent B-cells via contact-dependent mechanisms (Franquesa et al., 2015).  Manferdini et al., (2017) reported the switching of activated inflammatory M1 macrophages to M2 macrophage-like phenotype via prostaglandin E2 by adipose derived MSCs. Jiang et al., (2016) reported that MSCs can also prevent neutrophil death via an ICAM-1-dependent mechanism to further exert tissue-protective effects. In innate immune system, MSCs also exert their immunomodulatory properties via paracrine mechanisms by secreting multi-functional molecules (Zhou et al., 2019). MSC-derived exosomes and MSC-conditioned medium (CM) increases neutrophil viability and function thus useful for increasing immunity by modulating neutrophils (Mahmoudi et al., 2019). Although MSC-derived EVs (MSC-EVs) display immunoregulatory functions similar to the parent MSCs, their paracrine actions vary according to the source of the MSCs, the target cells and the microenvironment surrounding the cells (Xue et al., 2023). MSCs have also been shown to increase the ability of IL-12/IL-18-stimulated NK cells to secrete IFN-γ which has the ability to improve defense against infections at the site of injury besides influence tissue regeneration (Thomas et al., 2014).
 
Mesenchymal stem cells as a promising tool for drug delivery
 
The immunomodulatory properties of MSCs and their inherent capacity to selectively migrate towards inflammatory and neoplastic sites render them promising vehicles for targeted delivery of anti-tumor therapeutics, carriers for synthetic nanoparticles for drug delivery and favourable candidates for evolving genetic engineering and drug delivery strategies (Mei et al., 2024). The therapeutic potential of mesenchymal stem cells is being investigated for cancer therapy, inflammatory and fibrotic diseases among others. Wang et al., (2019) has shown delivery of drugs and therapeutic cytokines to the site of injury by drug-loaded and genetically modified mesenchymal stem cells and their derivatives. Pacioni et al., (2015) used MSCs as lung-targeting vectors loaded with doxorubicin nanoparticles and reported that the MSC/Nanoparticle delivery system inhibited the development of lung cancer effectively with a lower dose of anticancer drugs. Pan et al., (2022) reported that MSCs uptake diagnostic nanoparticles to specific targets thus can be used to track the labelled cells.
       
As carriers of anti-tumor drugs, MSCs can be genetically engineered to express or secrete a variety of therapeutic agents like therapeutic proteins, suicide genes and oncolytic viruses that inhibit cancer growth and progression. Studies have shown that MSCs engineered to co-express an antigen-specific domain (VHH) targeting epidermal growth factor receptor (EGFR) and death receptor (DR4/5) ligand (DRL) target both cell proliferation and death pathways in tumors (Zhu et al., 2017). Zhang et al., (2017) reported that MSCs engineered to express TandAb, a tetravalent bispecific tandem diabody, for CD3 and CD19 have enhanced therapeutic efficacy in a mouse model of B-cell lymphoma as compared to targeting CD3 or CD19 alone. Sirpilla et al., (2024) very recently used an E-cadherin-targeted chimeric antigen receptor to construct CAR-MSCs in an animal model to enhance immunosuppressive potency at sites of inflammation while maintaining their stem cell phenotype and safety. Seo et al., (2011) reported that IL-12-expressing MSCs can suppress the occurrence and progression of renal cell carcinoma and cervical cancer in mice.
 
MSCs future candidates for sustainable, economical and safe livestock production, food security and animal welfare
 
As already discussed in detail about the characteristics of MSCs, their all-in-one therapeutic potential and diverse applications in veterinary medicine have driven the attention of researchers, biotechnologists, clinicians and practitioners for its exploitation in every sphere of livestock medicine and production. MSCs are promising candidates for replacing the antibiotics and thus a promising tool against antimicrobial resistance. MSCs applications in regenerative medicine, inflammatory conditions, tumours, drug delivery, imaging and tissue engineering makes these plastic cells a central player in one health umbrella. The ease of harvesting MSCs from biological afterbirth waste and expanding them in-vitro without having any risk of teratogenesis or tumorigenesis or ethical issues or immune rejection, the MSCs can prove very economical biological tools for diverse applications in livestock, increasing their production potential, improving their health and minimising use of synthetic pharmaceuticals, thus making MSCs potential candidates for future sustainable food security and alternative biological source for alleviating antibiotic resistance.    

CONCLUSION

Mesenchymal stem cells are economically viable, ethically acceptable, procedurally non-invasive, immunologically inert and easily available from multiple sources. These cells are expandable in-vitro with no teratogenic effect and undergo senescence after certain cycles. These cells are plastic adherent with spindle shape, express stem cell markers and show trilineage differentiation. MSCs have typical homing properties that render them promising candidates for wound healing, osteoarthritis, ligament or tendon injury, drug delivery, diagnostic imaging and tumour therapy. Besides, MSCs are viable options in regenerative medicine, graft rejections, autoimmune diseases and cancers owing to their ability to evolve in different tissues, influence immunity through direct contact with the immune cells and/or through secretion of various bioactive molecules including cytokines, chemokines and growth factors. MSCs have been successfully used in livestock in wound healing, immune disorders, inflammatory conditions like osteoarthritis, mastitis, endometritis and replacement for antibiotics as well as therapeutic carriers. MSCs derived from livestock birth by-products shall prove economically viable and sustainable for large-scale veterinary applications including regenerative medicine, alternative medicine, drug delivery and diagnostics. It shall reduce bills in drugs and antibiotics and at the same time convert the waste of afterbirth into wealth thereby favouring the circular economy strategies and sustainable livestock production. It will be a promising technology in reducing the antibiotic resistance, approving one health concept and safeguarding nutritional food security. 

CONFLICT OF INTEREST

The authors have no conflict of interest to declare.

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    Review Article

    Mesenchymal Stem Cells-Their Immunomodulatory Potential and Clinical Applications in Veterinary Medicine: A Review

    Z
    Zahoor A. Pampori1,*
    A
    Aasif A. Sheikh1
    1Division of Veterinary Physiology, Faculty of Veterinary Sciences and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology-Kashmir, Srinagar-190006, Jammu and Kashmir, India.

    ABSTRACT

    Livestock is a crucial component of global animal husbandry that plays a vital role in sustaining human life and supporting the social and economic development. The application of stem cell technologies in livestock has demonstrated great potential to enhance productivity, improve animal welfare and support the sustainable development of animal husbandry practices. Among the stem cells, mesenchymal stem cells (MSCs) are one of the most promising cell populations owing to their multiple differentiation potential, homing property and immunomodulatory properties. This feature of plasticity makes MSCs favourable candidates for use in veterinary medicine. MSC therapy has potential in enhancing reproductive efficiency, improving overall production performance, addressing common injuries affecting bones, muscle and skin tissues through tissue specific differentiation, immunomodulation, secretion of diverse bioactive molecules and antimicrobial proteins. MSCs have been successfully used in tissue repair, wound healing, fractures, inflammation, mastitis, tissue grafts and organ transplants in livestock and companion animals. MSCs have recently been engineered and used as drug carriers to treat various tumours. The diverse properties of MSCs have evolved hope to combat antimicrobial resistance and treatment of diseases considered untreatable thus ensuring sustainable, organic, safe and nutritious food of animal origin. Of the utmost importance to MSC research is the identification of MSC sources that are easily obtainable, ethically acceptable, economically viable and stable. The livestock birth by-products such as umbilical cord, Wharton’s jelly, amniotic sac and amniotic fluid have been proposed as ideal sources of multiple stem cell lineages. The use of foetal adnexal tissue for isolation of MSCs has many potential advantages like the non-invasive nature of isolation, large tissue mass and ethical acceptance. In vitro expansion and differentiation potential of MSCs make these birth by-products as an attractive source of MSCs for regenerative therapies and biotechnological applications.

    INTRODUCTION

    In vitro cell culture technology has advanced significantly over last few decades and has attained robustness, reliability and maturity in its being used as a technology (Li et al., 2010). In-vitro cell culture has provided a commercial setup for production of therapeutic proteins or biomolecules. Cell culture technology has made advances and has become a key modelling system for large class of biotechnological interventions, clinical and industrial applications. Evans and Kaufman (1981) establishing a platform for pluripotent stem cells while harvesting mouse embryonic stem cells from mouse embryos. Stem cell culture has revolutionized the therapeutics and provided remedies to the diseases that were known to be untreated. Stem cell culture has also provided potential solution to regenerate the damaged tissue through paracrine secretions and/ or through the trans-differentiation or through integration and fusion with the native host cells (Xu et al., 2010). Stem cell therapy is gaining momentum to address various ailments that were earlier considered untreatable and its applicability has also spread tremendously through creation of stem cell banks, to safeguard new-borns against the impact of medical conditions. There are number of sources of stem cells either in adults or in foetuses or foetal appendages that are cultured in-vitro and directed to differentiate into desired type of cells for a particular treatment regime.

    Differentiation potential of cells
     
    In mammalian species, the union of male and female gametes at fertilization results into the formation of zygote/one cell embryo. The zygote or early cleavage stage blastomeres up to 4 cell stage has the potency to develop in a predictable manner into a complete species-specific adult organism, hence termed as totipotent cells (Aggarwal and Pittenger, 2005). The restriction in the potency occurs gradually as development proceeds. The cells of the late morula/early blastocyst/ inner cell mass (ICM) are pluripotent that are able to produce all or most of the cells of the body or all the derivatives of the three primary germ layers, however, are not capable of organizing and integrating them into a coherent adult body/organism. The germ-layer cells are much less plastic, referred as multipotent stem cells present in almost all the body tissues, that can give rise to limited number of cell types preferably of the same germ layer from which the stem cells are derived e.g. mesenchymal stem cells, haematopoietic stem cells (Krampera et al., 2007). As the embryo advances in its organization, the differentiation potential of cells gets restricted and the non-plastic version of cells, known as unipotent cells or somatic cells capable of dividing and giving rise to only its own cell type, are established (Pampori et al., 2024).
           
    Stem cells are non-specialized, undifferentiated cells having self-renewal capacity, excessive production and capability to differentiate into several types of highly specialized cells in the body (Fathi and Farahzadi, 2016). Friedenstein et al., (1970) cultured the bone marrow cells from rats and found them morphologically similar to fibroblasts, exhibiting plastic adherence. Three major types of stem cells that have been described are (i) Embryonic Stem Cells (ii) Adult Stem Cells and (iii) Induced Pluripotent Stem Cells (Table 1). Embryonic stem cells (ESC) are obtained from the inner cell mass of the blastocyst and are associated with tumorigenesis and ethical issues. The adult stem cells isolated from any adult tissue have invasive nature and are ethically unacceptable. Induced pluripotent stem cells (iPSC) can be obtained by inducing dedifferentiation of adult somatic cells through a recently developed in vitro technology known as cell reprogramming (Takahashi et al., 2007).

    Table 1: Types of stem cells and their characteristics.


           
    Besides the two common sources, the embryonic and the adult stem cells, extra-embryonic tissues (amnion, placenta and umbilical cord matrix) have been found as potential source of stem cells (Zhang et al., 2006). While evidence suggests that mesenchymal stem cells (MSCs) are present in almost all the tissues, they were first isolated from murine bone marrow by Friedenstein et al. (1966) and were termed as hematopoiesis-supporting cells in bone marrow. MSCs have been isolated from a variety of tissues such as bone marrow (Friedenstein et al., 1987), adipose tissue (Yang et al., 2010), birth-derived tissues (Gang et al., 2004), peripheral blood (Tondreau et al., 2005), Skin (Toma et al., 2005), muscle (Jackson et al., 2010), ovarian surface epithelium (Ajeet et al., 2022) etc.  (Fig 1). MSCs have been isolated and expanded in animal species like equines, canines, bovines, caprines and ovines. MSCs have been harvested successfully from equine bone marrow (Smith et al., 2003), adipose tissue (Vidal et al., 2008), peripheral blood (Giovannini et al., 2008) and umbilical cord blood (Reed et al., 2008). MSCs have been successfully harvested from cord blood by Raoufi et al., (2011) in bovine, by Shah et al., (2023) in ovines and by Ajeet et al., (2022) in canines. MSCs have been isolated and expanded in vitro from umbilical cord blood, amniotic fluid, Wharton’s jelly and amniotic membrane in sheep (Shah et al., 2023). MSCs were isolated from ovine foetal adnexa differentiated into three lineages viz. chondrogenic, osteogenic and adipogenic using differential media and retained the stemness after cryopreservation, thus opening a new window of cryopreservation of MSCs for future application in medicine (Khan, 2023 and Safia, 2023).

    Fig 1: Different sources of MSCs and their differentiation potential.


     
    Characteristics of mesenchymal stem cells
     
    Mesenchymal stem cells (MSCs) are stromal cells having the ability to self-renew, with multipotency, accessibility and immunomodulatory attributes. They can expand ex vivo in culture and differentiate into osteogenic, chondrogenic, adipogenic, myogenic cells and other lineages (Wei et al., 2013). MSCs are plastic adherent with typical spindle morphology, form clusters, besides express CD73, CD90 and CD105 and lack CD45, CD34, CD19, CD14 and CD3 the most important hematopoietic markers (Baghaei et al., 2017). Ruan et al., (2022) reported the homing property of MSCs and traced their migration, colonization and survival in Tree Shrew. Besides getting differentiated into various cell types, MSCs are reported to have immuno-modulatory competence which is predominantly exerted by a synergy of cell contact-dependent processes and soluble factors (Gnecchi et al., 2016). MSCs unlike ESCs and iPSCs have minimal teratogenicity, ethical issues and immune rejection.  They often lack major histocompatibility complex (MHC-II), prevent T-cell responses via the modulation of dendritic cells and disruption of natural killer (NK) cells that makes MSCs preferred therapeutic candidates (Spaggiari et al., 2008). MSCs in converse to Embryonic stem cells (ESCs) have restricted culture lifespan and after certain culture passages these cells become senescent (Caplan, 2017). Even upon in vivo implantation, MSCs (autologous/allogeneic) survive only for certain period (ranging from few hours to as long as 90 days) but not for an indefinite period (Eggenhofer et al., 2012).
     
    Non-expensive, non-invasive and attractive source of mesenchymal stem cells
     
    Owing to the unique characteristics of MSCs and their application in regenerative medicine, the research in obtaining these cells in large numbers in an inexpensive and non-invasive way without any risk to the donor has been identified in gestational or foetal adnexal tissues like foetal membranes, foetal fluid, umbilical cord matrix and cord blood. Stem cells obtained from these commonly referred “biohazardous afterbirth waste” are attractive candidates of MSCs. The adnexal tissue cells preserve some of the characteristics of the primitive embryonic layers from which they originate. The feasibility to collect large numbers of cells in an inexpensive, non-invasive way and the ability to cryogenically bank and expand the cells in vitro are important considerations to harvest the MSCs from foetal adnexa for use in regenerative medicine. The ease of harvest and the quantity obtained make these sources most practical for experimental and possible clinical applications. There are likely more sources of MSCs waiting to be discovered that may prove good candidates for future experimental or clinical applications.
           
    MSCs isolated from foetal adnexa have been reported to express specific pluripotent and MSC markers. Wharton’s Jelly or umbilical cord matrix-derived stem cells are present in relatively high numbers as compared to routinely isolated from adult bone marrow. Carlin et al., (2006) and Shah et al., (2023) emphasized that Wharton’s jelly is an easy and inexpensive source of stem cells based on the expression of transcription factors of pluripotency, adherence to plastic growth plates, colony-forming ability and in vitro expansion.
     
    Therapeutic potential of mesenchymal stem cells
     
    Stem cell culture has revolutionized the therapeutics and provided remedies to the diseases that were known to be untreated. Stem cell culture has also provided potential solution to regenerate the damaged tissue through paracrine activities and/or through the trans-differentiation or through integration and fusion with the native host cells (Pampori et al., 2024). Mesenchymal stem cells (MSCs) are considered the most promising cell populations for regenerative medicine and tissue engineering as the cells carry all in one therapeutic solution for diverse clinical disorders attributable to their characteristic properties such as self-renewal, multiplication, immune-modulation and multi-lineage differentiation potential (Gugjoo et al., 2017). However, lack of regulatory set up in India makes MSCs therapeutic applications in veterinary medicine a more complicated field (Gugjoo et al., 2022).
           
    Non-embryonic extra-foetal derived stem cells have opened new perspectives for developmental biology and for regenerative medicine and have demonstrated variable differentiation potential based upon their tissue sources. Safia (2023) reported a source bias in the trilineage differentiation of ovine MSCs, cells from amniotic fluid exhibited highest adipogenic potential whereas MSCs from cord blood outperformed in chondrogenic and osteogenic potential determined as relative transcript abundance of lineage specific markers in the in vitro expanded MSCs which enables choice-based use of MSCs in regenerative medicine. Khan (2023) successfully cryopreserved the in vitro expanded ovine MSCs derived from foetal adnexa in liquid nitrogen and reported normal growth and stem cell marker expression post-thaw indicating that MSCs could be exploited for stem cell banking and future use in regenerative medicine.
     
    Clinical application of mesenchymal stem cells in veterinary medicine
     
    Presently, stem cell technology is being considered to carry potential to effectuate tissue regeneration through paracrine activities and/or through trans-differentiation (Xu et al., 2010). Foubert et al. (2017) reported that MSCs are normally present in the skin and are actively involved in its natural regeneration. They prevent hypertrophic scarring seen in chronic wounds and recurrent teat injuries through production of anti-fibrotic factors in porcine model. Stem cells have revealed significant promise in regenerating orthopaedic tissues in livestock such as cartilage (chondrogenesis), tendons and bones. This makes them a viable treatment option for conditions like osteoarthritis and mandible defects. Richardson et al., (2007) used MSCs derived from bone marrow and adipose tissue in treatment of strain-induced tendon injury in the horse and the outcome was encouraging as compared to the present therapeutic approaches. Carlier et al., (2024) used tenogenic primed MSCs intralesionally in sport horses having superficial digital flexor tendon and suspensory ligament injuries and reported safe and improved quality of healing and long-term outcomes, thus MSC therapy in high value racehorses can be a viable option to treat them. Yaşar and Perk (2023) reported significant improvement in osteoarthritis in dogs treated with MSCs which can replace the use of steroid and NSAID in such conditions. Jammes et al. (2023) reported that exosomes from MSCs primed with proinflammatory cytokines were promising therapy in treating osteoarthritis in equines. In goats Yu et al., (2021) employed bone mesenchymal stem cells on a scaffold in temporomandibular joint condyle defects and demonstratied efficiency of MSCs in correction of condyle defects. MSCs in veterinary medicine have been used to treat cartilage injury of dogs and horses (Ganiev et al., 2021). Bhat et al., (2019) revealed that MSCs can be safely used allogenically for spinal cord injury where the conventional medication is not promising and treated 44 clinical cases of spinal cord injury dogs with encouraging results. Bhatt et al., (2021) reported encouraging results in full thickness wound healing in Guinea pigs treated with MSCs. Gugjoo et al., (2020) reported that combined use of MSCs and growth factors could accelerate osteochondral healing in rabbits.
           
    Pokorska et al., (2024) and Peralta et al., (2020) demonstrated that the MSCs administered either intravenous cum intramammary or intramammary only reduced the bacterial growth as well as somatic cell count in milk samples and were effective in reducing bovine mastitis without use of antibiotics. Harman et al., (2017) demonstrated that equine MSC inhibit bacterial growth through production of antimicrobial proteins in treatment of wounds in equines and human. Cahuascanco et al., (2019) reported that conditioned media from foetal bovine bone marrow and adipose tissue derived MSC has the capacity to reduce in average ~30% of S. aureus growth under in vitro conditions and can be a promising source of treating mastitis replacing antibiotics. Del Prete et al. (2024) demonstrated an overall positive effect of MSCs therapies in treating endometritis in equines through anti-inflammatory effect, reduced intrauterine fluid accumulation and cytokine concentrations with improvements in pregnancy, foaling and embryo recovery rates. Meissner et al., (2024) demonstrated that MSCs-derived extra cellular vesicles represent an innovative and promising therapeutic approach in treatment of corneal ulcers in horses.
           
    Despite the pronounced advances over the past few decades in medicine, organ transplant technique still faces significant obstacles. MSCs from autologous and allogeneic sources are being used in transplant recipients to reduce the use of immunosuppressive drugs and thereby protect against graft rejection. Mesenchymal stem cells have a specific impact on the characteristics of transplantation and regenerative medicine thus emerging as a powerful tool in regenerative medical field.
     
    Immune-modulatory functions of mesenchymal stem cells
     
    MSCs participate in both innate and adaptive immunity and their immunomodulatory functions are exerted mainly via direct contact with immune cells (cell-to-cell contact) and through local micro-environmental factors (paracrine activity). MSCs are reported to cause modulation in lymphocyte proliferation, regulation of B-cell proliferation and function, induction of regulatory T-cell proliferation, inhibition of dendritic cell and natural killer cell activation (Spaggiari et al., 2006). MSCs inhibit T-cell proliferation induced by mitogens, CD3 and CD28 antibodies as well as allogeneic antigens (Devine et al., 2003). Co-culture of peripheral blood mononuclear cells (PBMCs) with MSCs causes shift from allogenic T-cell responses to the secretion of a Th2 cytokine profile and inhibition of cytotoxic lysis of allogeneic cells through induction of CCL1 and sHLA-G. MSCs have been shown to modulate immune responses by the de novo induction and expansion of CD4+, CD25+, FoxP3+ and CD8+ regulatory T-cells (Tregs) which are responsible for inhibiting allogeneic lymphocyte proliferation (Maccario et al., 2005). 
           
    MSCs possess the capacity to block the proliferation of activated B-cells in the presence of IFN-γ and negatively interfere with antibody production (Bernardo et al., 2009). MSCs inhibit IL-2-induced NK cell proliferation which is primarily mediated by the soluble immunosuppressive factors TGF-β, sHLA-G and PGE-2 as well as cell-cell contact (Shi et al., 2011). MSCs also prevent NK cell effector functions like cytotoxicity against virus-infected cells through reduced IFN-γ secretion. MSCs interact with NK cells and influence the cytokine production through secretion of IDO (Indoleamine-2,3-Dioxygenase) and PGE-2 (Spaggiari et al., 2008). MSCs have been reported to down-regulate the expression of CD40, CD80, CD83 and CD86 on dendritic cells that interfere with their differentiation from CD14+ monocytes and CD34+ progenitor cells. Dendritic cells produced in the presence of MSCs secrete low levels of IL-12 and TNF-α, but high levels of IL-1β and IL-10, besides low expression levels of MHC class-II surface antigen indicating that antigen processing and presentation via MHC class-II surface antigens is impaired (Nauta et al., 2006).
           
    Several studies have ascertained that the immunomodulatory effects of MSCs are mainly linked to MSC-secreted cytokines. The expression of TLR3 and TLR4 in MSCs has been shown to restore an efficient T-cell response to infection (Liotta et al., 2008). MSCs also affect B-cells through cell-to-cell contact and have shown to increase the survival of quiescent B-cells via contact-dependent mechanisms (Franquesa et al., 2015).  Manferdini et al., (2017) reported the switching of activated inflammatory M1 macrophages to M2 macrophage-like phenotype via prostaglandin E2 by adipose derived MSCs. Jiang et al., (2016) reported that MSCs can also prevent neutrophil death via an ICAM-1-dependent mechanism to further exert tissue-protective effects. In innate immune system, MSCs also exert their immunomodulatory properties via paracrine mechanisms by secreting multi-functional molecules (Zhou et al., 2019). MSC-derived exosomes and MSC-conditioned medium (CM) increases neutrophil viability and function thus useful for increasing immunity by modulating neutrophils (Mahmoudi et al., 2019). Although MSC-derived EVs (MSC-EVs) display immunoregulatory functions similar to the parent MSCs, their paracrine actions vary according to the source of the MSCs, the target cells and the microenvironment surrounding the cells (Xue et al., 2023). MSCs have also been shown to increase the ability of IL-12/IL-18-stimulated NK cells to secrete IFN-γ which has the ability to improve defense against infections at the site of injury besides influence tissue regeneration (Thomas et al., 2014).
     
    Mesenchymal stem cells as a promising tool for drug delivery
     
    The immunomodulatory properties of MSCs and their inherent capacity to selectively migrate towards inflammatory and neoplastic sites render them promising vehicles for targeted delivery of anti-tumor therapeutics, carriers for synthetic nanoparticles for drug delivery and favourable candidates for evolving genetic engineering and drug delivery strategies (Mei et al., 2024). The therapeutic potential of mesenchymal stem cells is being investigated for cancer therapy, inflammatory and fibrotic diseases among others. Wang et al., (2019) has shown delivery of drugs and therapeutic cytokines to the site of injury by drug-loaded and genetically modified mesenchymal stem cells and their derivatives. Pacioni et al., (2015) used MSCs as lung-targeting vectors loaded with doxorubicin nanoparticles and reported that the MSC/Nanoparticle delivery system inhibited the development of lung cancer effectively with a lower dose of anticancer drugs. Pan et al., (2022) reported that MSCs uptake diagnostic nanoparticles to specific targets thus can be used to track the labelled cells.
           
    As carriers of anti-tumor drugs, MSCs can be genetically engineered to express or secrete a variety of therapeutic agents like therapeutic proteins, suicide genes and oncolytic viruses that inhibit cancer growth and progression. Studies have shown that MSCs engineered to co-express an antigen-specific domain (VHH) targeting epidermal growth factor receptor (EGFR) and death receptor (DR4/5) ligand (DRL) target both cell proliferation and death pathways in tumors (Zhu et al., 2017). Zhang et al., (2017) reported that MSCs engineered to express TandAb, a tetravalent bispecific tandem diabody, for CD3 and CD19 have enhanced therapeutic efficacy in a mouse model of B-cell lymphoma as compared to targeting CD3 or CD19 alone. Sirpilla et al., (2024) very recently used an E-cadherin-targeted chimeric antigen receptor to construct CAR-MSCs in an animal model to enhance immunosuppressive potency at sites of inflammation while maintaining their stem cell phenotype and safety. Seo et al., (2011) reported that IL-12-expressing MSCs can suppress the occurrence and progression of renal cell carcinoma and cervical cancer in mice.
     
    MSCs future candidates for sustainable, economical and safe livestock production, food security and animal welfare
     
    As already discussed in detail about the characteristics of MSCs, their all-in-one therapeutic potential and diverse applications in veterinary medicine have driven the attention of researchers, biotechnologists, clinicians and practitioners for its exploitation in every sphere of livestock medicine and production. MSCs are promising candidates for replacing the antibiotics and thus a promising tool against antimicrobial resistance. MSCs applications in regenerative medicine, inflammatory conditions, tumours, drug delivery, imaging and tissue engineering makes these plastic cells a central player in one health umbrella. The ease of harvesting MSCs from biological afterbirth waste and expanding them in-vitro without having any risk of teratogenesis or tumorigenesis or ethical issues or immune rejection, the MSCs can prove very economical biological tools for diverse applications in livestock, increasing their production potential, improving their health and minimising use of synthetic pharmaceuticals, thus making MSCs potential candidates for future sustainable food security and alternative biological source for alleviating antibiotic resistance.    

    CONCLUSION

    Mesenchymal stem cells are economically viable, ethically acceptable, procedurally non-invasive, immunologically inert and easily available from multiple sources. These cells are expandable in-vitro with no teratogenic effect and undergo senescence after certain cycles. These cells are plastic adherent with spindle shape, express stem cell markers and show trilineage differentiation. MSCs have typical homing properties that render them promising candidates for wound healing, osteoarthritis, ligament or tendon injury, drug delivery, diagnostic imaging and tumour therapy. Besides, MSCs are viable options in regenerative medicine, graft rejections, autoimmune diseases and cancers owing to their ability to evolve in different tissues, influence immunity through direct contact with the immune cells and/or through secretion of various bioactive molecules including cytokines, chemokines and growth factors. MSCs have been successfully used in livestock in wound healing, immune disorders, inflammatory conditions like osteoarthritis, mastitis, endometritis and replacement for antibiotics as well as therapeutic carriers. MSCs derived from livestock birth by-products shall prove economically viable and sustainable for large-scale veterinary applications including regenerative medicine, alternative medicine, drug delivery and diagnostics. It shall reduce bills in drugs and antibiotics and at the same time convert the waste of afterbirth into wealth thereby favouring the circular economy strategies and sustainable livestock production. It will be a promising technology in reducing the antibiotic resistance, approving one health concept and safeguarding nutritional food security. 

    CONFLICT OF INTEREST

    The authors have no conflict of interest to declare.

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