Applications and Uses of Stem Cells in Regenerative

Medicine: An Overview of Wound Healing

Deependu PS (536) | Shravana B (617) | N Sravya (353)
Hindu College, University of Delhi

1. Introduction

Cells with the ability to divide and regenerate themselves are known as stem cells (Coghlan,
2009). By definition, all stem cells are ‘undifferentiated’, meaning they can develop into a
variety of specialised cells, at least theoretically (Coghlan, 2009). Stem cells are classified
according to their origin and capacity of differentiation, respectively. Based on origin, they
are divided into 1. Embryonic stem cells, as an embryo grows and develops into a baby,
embryonic stem cells supply new cells. 2. Adult stem cells, adult stem cells, also
called somatic cells, are stem cells which maintain and repair the tissue in which they are
found (Nolan, 2022). 3. Induced pluripotent stem cells are adult cells that have been
converted into pluripotent stem cells by adding a limited number of particular
genes(Laflamme et al., 2007). Induced Pluripotent stem cell technology, which allows for the
creation of pluripotency in mature somatic cells through the application of specific stimuli,
has opened up new possibilities in basic research, disease modelling, and regenerative
medicine (Takahashi & Yamanaka, 2006).

Stem cells are further divided into Totipotent, Pluripotent, and Multipotent categories based
on their differentiation potential. Multipotent stem cells are able to differentiate into any cell
type within a single lineage and they play an important role in the development, repair, and
protection of tissues (Multipotent Stem Cell - an Overview | ScienceDirect Topics, n.d.). A
totipotent cell, according to the formal definition, is a single cell that, with sufficient maternal
support, can give rise to a new organism, while a less proper definition is a cell that can give
rise to all extraembryonic tissues as well as all body tissues and the germline (Baker & Pera,
2018). Pluripotent stem cells can self-renew and give rise to all types of cells in the body's
tissues (Romito & Cobellis, 2016). ESCs are produced from the ICM of preimplantation
embryos (Evans & Kaufman, 1981) (Thomson, 1998) and can be kept and developed in the
pluripotent condition in vitro indefinitely. Pluripotent stem cells can also be created in vitro
by dedifferentiating adult somatic cells via a procedure known as cell reprogramming
(Takahashi & Yamanaka, 2006) (Takahashi et al., 2007).

Stem cell treatment is a type of regenerative medicine that involves lowering inflammation
and modifying the immune system in order to heal damaged cells within the body and could
be used to generate new cells that can then be transplanted back into the body to replace those
that have been injured or lost (Biehl & Russell, 2009). “Because many of the early animal
trials resulted in the undesirable creation of rare solid tumours termed teratomas, pluripotent
stem cells have not yet been employed therapeutically in humans” (Biehl & Russell, 2009).

2. Stem cell therapy

The use of stem cells to repair or prevent disease is referred to as stem-cell therapy (Mahla,
2016). At the beginning of 2015, hematopoietic stem cell transplantation was the only
established stem cell therapy (Müller et al., 2016). The cells can be obtained from umbilical
cord blood or bone marrow transplantation. Multiple stem-cell sources are being developed,
as well as stem-cell therapy for neurological diseases (Lyon, 2018) and disorders like
diabetes and heart disease.

3. Medical Uses

Hematopoietic stem cell transplantation (HSCT) has been used to treat persons with
leukaemia and lymphoma for over 30 years; it is the only extensively utilised kind of stem-
cell therapy (Blood-Forming Stem Cell Transplants What Are Bone Marrow and Hematopoietic
Stem Cells? Why Are BMT and PBSCT Used in Cancer Treatment?, n.d.)(Karanes et al., 2008).
Stem cell therapy can be potentially used to reverse the side effects of chemotherapy by
replacing the lost cells. In 2012, Prochymal, a stem-cell therapy, was provisionally licenced
in Canada for the treatment of acute graft-vs-host disease in children who were not
responding to steroids (Rattue, 2012). It's an allogenic stem cell therapy that uses
mesenchymal stem cells (MSCs) obtained from adult donors' bone marrow and they are
extracted from the bone marrow, cultivated, and packed, with a single donor yielding up to
10,000 doses, these are kept frozen until they are needed (Andrew, 2012). The European
Medicines Agency suggested that limbal stem cells be approved for persons who have
significant limbal stem cell insufficiency owing to ocular burns in 2014 (First stem-cell
therapy recommended for approval in EU, 2014).

4. Applications

The use of stem cells in regenerative medicine has a wide range of applications in tissue
regeneration and disease treatment. Some of the applications are listed below:

Figure 1. A diagram of human stem cell applications (Butt, 2018).

Neurodegeneration

Animal models of brain degeneration, such as Parkinson's disease, Amyotrophic lateral

sclerosis, and Alzheimer's disease, have been studied for the effects of stem cells (Neural
Stem Cells May Rescue Memory In Advanced Alzheimer's, Mouse Study Suggests, 2009)
(Vastag, 2001). Preliminary studies on multiple sclerosis have been conducted (Rebeiro &
Moore, 2016) (Abdallah et al., 2019) and a 2020 phase 2 experiment indicated that patients
who received mesenchymal stem cell treatment had considerably better outcomes than those
who received a sham treatment (Petrou et al., 2020). The first clinical trial for an
investigational stem cell therapy to replace damaged brain cells in persons with severe
Parkinson's disease was approved by the FDA in January 2021 (Upcoming Clinical Trial Will
Test New Cell Therapy for Parkinson’s Disease in Humans, 2021).

Frailty syndrome

After intravenous therapy with MSCs from healthy young donors, persons 60 years or older
with ageing frailty exhibited significant improvements in physical performance assessments
(Tompkins et al., 2017).

Brain and spinal cord injury

Stroke and traumatic brain damage cause cell death in the brain, which is defined by the loss
of neurons and oligodendrocytes and use of this stem cells in cases of spinal cord damage has
been studied in both clinical and animal trials (Abdallah et al., 2019; Cummings et al., 2005;
Kang et al., 2005).

Heart Disease

In persons with serious heart disease, stem cells are being examined (Ptaszek et al., 2012).
Hundreds of factual discrepancies were discovered in the work of Bodo-Eckehard Strauer
(Francis et al., 2013; Strauer & Steinhoff, 2011) . Only a few research have found genuine
evidence of benefit among multiple clinical trials claiming that adult stem cell treatment is
safe and effective (Brehm M et al., 2008). The use of bone marrow stem cell treatment
resulted in very minor improvements in heart function in certain exploratory clinical trials
(Kuswardhani & Soejitno, 2011; Malliaras et al., 2011).

Regrowing teeth

In 2004, researchers at King's College London developed a means to create a whole tooth in
mice, allowing them to produce bioengineered teeth in the lab (Highfield, 2004).

Cochlear hair cell regrowth

With the use of embryonic stem cells, Heller was able to re-grow cochlea hair cells.
Stem cell-derived otic progenitors have the potential to dramatically improve hearing,
according to a 2019 review of hearing regeneration and regenerative medicine (Nacher-Soler
et al., 2019).

Pancreatic beta cells

In theory, if a diabetic patient's beta cells are transplanted effectively, they will be capable of
replacing faulty ones (Saki et al., 2013).

Orthopedics
Preliminary research into the use of mesenchymal stem cells (MSCs) produced from adult
stem cells for prospective orthopedic applications in bone and muscle damage, cartilage
healing, osteoarthritis, intervertebral disc surgery, rotator cuff surgery, and musculoskeletal
disorders is now underway (Berebichez-Fridman et al., 2017).

HIV/AIDS

Scientists are now investigating a novel method of treating HIV/AIDS that includes the
transplantation of allogeneic, gene-modified (HIV-1-resistant) hematopoietic stem and
progenitor cells to generate a disease-resistant immune system (Digiusto et al., 2013).

Wound Healing
Stem cells also can be employed to help human tissues grow faster. Scar tissue, which is
characterised in the skin by disorganised collagen structure, loss of hair follicles, and uneven
vascular structure, replaces injured tissue in adults. Wounded fetal tissue, on the other hand,
gets replaced with normal tissue because of the activity of stem cells (Gurtner et al., 2007).
Place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem
cells to drive differentiation in the tissue bed cells as a possible technique for tissue
regeneration in adults, such regenerative response elicited by this approach is more related to
prenatal wound repair than adult scar tissue formation (Gurtner et al., 2007). Stem cells have
gained popularity as a treatment for cutaneous wounds, such as skin cancer, due to their
general healing powers (Rognoni & Watt, 2018).

5. Skin tissue regeneration

Skin tissue is the most superficial layer of tissue that acts as the first and primary barrier of
protection. The skin tissue consists of three layers which are epidermis, dermis and
hypodermis (Lamberty & Cormack, 1994). The epidermis forms the outermost layers and
acts as a waterproof barrier. It plays an important role in regulating the entry of moisture into
the boy (Natarajan et al., 2014). Next comes the dermis which accounts for 90% of the
weight of skin (Pappas, 2015). It is the layer between the epidermis and the hypodermis
(Gaboriau & Murakami, 2001). This layer is followed by the hypodermis which is the deepest
layer of the skin tissue. The hypodermis is abundant in proteoglycans and
glycosaminoglycans. This enables the layer to absorb fluid into the tissue and gives it mucous
like properties (Wong et al., 2016).

Wounds and wound healing

Any injury to the skin tissue may disrupt its functions. A wound maybe any disorder in the
natural structure of the skin tissue which can also disrupt the functioning of the underlying
tissue of the body (Reinke & Sorg, 2012). Wound can broadly be classified into open and
closed wounds (Velnar et al., 2009). Base on the time taken for wound healing and repair,
wounds can be of two types, acute and chronic (Velnar et al., 2009). Chronic wounds take
more time for healing than acute wounds due to inflammation (Stadelmann et al., 1998).
Stem cells can be used in order to improve the quality of wound repair. The use of stem cells
for wound healing may result in acceleration in wound healing, earlier closure of the wound
and regeneration of skin and its appendages (Butler et al., 2010). Stem cells are used in
therapy because they have the capability to secrete pro-regenerative cytokines which help
accelerating the treatment of chronic wounds (Duscher et al., 2016). The embryonic stem
cells, induced pluripotent stem cells and adult stem cells are the main sources of stem cells
that are used for wound healing and regeneration of injured skin tissue (Dash et al., 2018).
Location of stem cells in skin epithelium
There is no specific morphological region where the stem cells are located. Initially scientists
came up with a hypothesis that the stem cells are found in the basal layer of the skin
epithelium (Potten et al., 1979). It was found out that 2-7% of the basal layer cells are
composed of stem cells (Potten et al., 1979). In order to demonstrate the presence of stem
cells in cultures of epidermal cells, the population has to be labeled and then must be used to
reconstitute an epidermal tissue in vivo. When retrovirally tagged murine epidermal cultures
expressing the β-galactosidase reporter gene were transplanted into a mouse, the
reconstructed skin showed clonal columns of β-galactosidase expressing epidermal cells
(Mackenzie, 1997). Over a period of 12 weeks of study it was found out that 10-12%of the
murine basal layer cells might be stem cells which had the ability to produce a single column
of maturing cells. Another method to identify the presence of stem cells is by making use of
their slow cycling nature. All proliferating cells of a tissue incorporate nucleotide analogues
such as bromodeoxyuridine or titrated thymidine into newly manufactured DNAs in a pulse-
chase experiment. Only those cells that divide rarely are situated in the tissue retain their
label, when their label is chased. In the oral epithelium such label retaining tissues are found
within the tongue and palatal papillae. As a result, in the 1980s, a model of skin epithelial
maintenance emerged, in which the periodic division of slow cycling stem cells in the basal
layer gives rise to transiently amplifying cells that populate the majority of the basal layer,
dividing two or three times before differentiating into mature skin cells.

6. Stem cells used in wound therapy

Bone marrow stromal cells are used in the process of wound closure. These stem cells
stimulate fibroblasts and the migration of keratinocytes and ECM protein synthesis. It takes
about 3 days for the wound to get healed completely (Walter et al., 2010).
-Autologous mesenchymal stem cells (MSCs) are used in the treatment of cutaneous wounds.
They are introduced by fibrin spray system. They basically stimulate closure of thick wounds
in diabetic mice. They also help in wound repair. They cure the wound in about 12 weeks
(Falanga et al., 2007).
- Autologous bone marrow cells help in rebuilding the dermal cells. These stem cells are used
in treating chronic wounds. The wound can be completely treated in a time span of 5 weeks
(Badiavas & Falanga, 2003).

- Allogenic bone marrow stromal cells (BM-SCs) help in treating excisional wounds. They
accelerate the closure of the wound, increase the epithelialization of the wound. They cure
the wound in about 14 days (Wu et al., 2007).
- Human embryonic stem cells (hESCs) play a major role in the process of advanced wound
healing. They help in treating burns. The mode of delivery of these stem cells is through
grafting. The hESC- derived epidermis had shown a pluristratified structure of the skin
(Guenou et al., 2009).
 - Pluripotent stem cells help in curing skin diseases. They cause reconstitution of
normal skin structures. After treatment, skin appendages such as hair follicles and
glands had no cyst or tumor formation (Itoh et al., 2013).

7. Role of stem cells in cutaneous wound healing

Adult stem cells (ASCs) are regarded as crucial participants in tissue regeneration because
they represent a source for replenishing lost cells during wound repair. Because ASCs have
been found in almost every tissue type in the human body, and their use for regenerative
medicine purposes raises far fewer ethical concerns than the use of embryonic stem cells, and
therapies involving autologous ASCs pose no risk, the field of basic ASC research and its
clinical applications to regenerative medicine has seen rapid growth. Normal wound healing
is a vital survival component, both in the individual and the species as a whole, because skin
serves various tasks, including acting as a barrier to invading pathogens, controlling body
temperature, supplying feeling, and preventing dehydration (Clarck, 1988; Haake & Holbrook,
1999; Martin, 1997; yu et al., 2006). Burn injury is another sort of skin insult that can be
potentially fatal, but also has depleting effects on local tissue stem cells, making it difficult
for the wound to heal on its own, necessitating the use of borrowed skin from another body
location to restore the skin's functions (Garrison et al., 1995; Piatkowski et al., 2009). The
goal of skin wound healing is to repair a skin defect and, at least in part, restore the skin's
integrity, tensile strength, and barrier function (Singer et al., 2000). The wound healing
process is divided into three phases: inflammatory, proliferative, and tissue remodelling, all
of which lead to scar formation (Werner & Grose, 2003).

Inflammatory cell precursors from bone marrow, hair follicle and dermis
The BM-mesenchymal stem cells (MSC) have been demonstrated to have a role in this stage
of wound healing, since they use the Notch signalling pathway to regulate the differentiation
of haematopoietic progenitor cells (HPC) into dendritic cells(Li et al., 2008). The
requirement for leucocytes is at least partially met because to this interaction and the ability
to allow myelopoiesis during the early inflammatory phase.

Mesenchymal-to-epithelial transition (MET)

The phenomena of a cell moving from a mesenchymal to an epithelial phenotype is known as
mesenchymal-to-epithelial transition (MET); the opposite is known as epithelial-to-
mesenchymal transition (ETM)(Mani et al., 2008). During embryonic skin growth, tissue
regeneration, and wound healing, both processes are critical (Savagner et al., 2005). MET
isn't just for skin; it's also essential for the de novo formation of a hair cell in the ear, for
example (Hu & Corwin, 2007). The ability of mesenchymal multipotent progenitors in the
mouse dermis to develop into keratinocytes has been discovered (Crigler et al., 2007). As a
result, it's worth seeing if some of these dermal (mesenchymal) progenitor cells can assist
reepithelialize the lesion in vivo using MET.

Revascularization by resident and circulating endothelial cell precursors

The predominant route of revascularization in normal wound healing (Bluff et al., 2007) is
angiogenesis, which is essentially dependent on the sprouting of resident ECs. Tissue-
resident endothelial precursors (TEPs), which were recovered from murine adipose tissue and
dermis (Grenier et al., 2007), and pluripotent nestin expressing cells have recently been found
as new stem cell types with angiogenic capacity (Amoh et al., 2004). Although not known to
create nascent blood vessels during normal wound healing, adipose-derived stem cells
(ADSC) are multipotent stem cells that can develop into EC and promote angiogenesis
(Altman et al., 2008). Angiogenesis in deeper wounds may be aided by them. They may aid
angiogenesis in more serious wounds.

BM-derived stem cells, hair follicle and dermal MSC contribute to the final
phase of healing

The origin of BM-derived fibroblasts in the skin has long been a point of contention. BM-
derived fibrocytes, on the other hand, penetrate the wound early in the healing process and
express the ECM proteins vimentin, collagen I, and III (Bucala et al., 1994; Quan et al.,
2004). BM-derived mesenchymal cells (MC) on the other hand, were discovered to take on a
fibroblast cell fate in vivo in mice during cutaneous wound healing and to express the
fibroblast-specific collagen I-2 chain in vivo (Opalenik & Davidson, 2005) as well as both the
collagen I and III genes in vitro(Fathke et al., 2004; Opalenik & Davidson, 2005).

Repigmentation
After wound closure, a well-healed wound can be repigmented (Ho et al., 2000; Pepper,
1954) and even have its appendages reconstructed Billingham et al., 1959; Ito et al., 2007).
The amelanotic melanocytes in the HF-ORS, which come from melanocyte stem cells
(melSC) located in the HF bulge and sub-bulge, are now assumed to represent the cell pool
responsible for epidermal repigmentation(Nishimura et al., 2002).

Hair follicle neogenesis

Full-thickness excisional wounds in mice were discovered to heal with de novo HF
production, despite the fact that this has yet to be demonstrated in damaged human skin. This
process requires functional Wnt signalling (Ito et al., 2007). This is consistent with previous
findings that skin appendage neogenesis occurs in adult deer antlers (Billingham et al., 1959)
and damaged rabbit skin (Billingham & Russell, 1956).

8. Discussion and future perspectives

Stem cells are special kind of cells that have the ability to form different types of cells. Stem
cells are divided into different types based on functions as well as based on sources. The
usage of stem cells or their derivatives,
increases the repair response of sick, malfunctioning, or wounded tissue.
Stem cells can be manipulated to become specific cells that can be used to regenerate and rep
air tissues that have been destroyed or affected by disease in people. Stem cell therapy ,
which may also called as regenerative medicine that helps to cure or repair damaged tissues
by different processes. It can be used in various medicinal fields including the treatment for
neurodegeneration, brain and spinal injury, heart disease, wound healing etc. The ability of
stem cells to regenerate tissues can be used for skin repairing and after skin burn injury. The
ability of skin epidermal layer to regrow is because of the presence of epidermal stem cells
and they divide to form keratinized layer that act as barrier. The main goal for this regrowing
and usage of stem cells is applicable for dermatology as well. The stem cell therapy is rapidly
growing in treatment and its future demand is more. In this review article the overview of
stem cells and their applications in various fields specifically in wound healing have been
discussed. A primary goal of this stem cells to identify how undifferentiated stem cells
become the differentiated cells that form the tissues and organs. Stem cells have provided the
science with a lot of hope for further research. Exploring more in this field can pave the path
for the treatment of various other conditions such as Alzheimer’s, Parkinson's, diabetes and
many more. In short stem cells can be the future of science in the coming years.

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