79 Stem Cell Therapy

R.D. Lele

KEY MESSAGE Blastocyst Liver, GIT, lungs

Endoderm
• Stem cells are immortal cells, which have the
Mesodermal
potential to divide indefinitely. progenitor cell
Embryonic stem cells Mesoderm
• Intradermal injection of allogeneic fibroblasts Hemopoietic BM
in the lesional skin of patients with recessive Human blastocyst
progenitor cell
dystrophic epidermolysis bullosa has shown Trophoblast Skin,
improvement in skin fragility. Ectoderm CNS
• Autologous bone marrow derived cultured Blastocoel

mesenchymal stem cells have been used in Zona Embryoblast

the management of ulcers. pellucida

Fig. 79.1: Stem cell differentiation.

INTRODUCTION A new discovery is the presence of resident stem

cells in the liver, kidneys, skeletal and cardiac
Stem cells are cells which have the ­ potential ­muscle, endothelial progenitor cells (EPCs), d
­ ental,
to divide indefinitely and are required to renew retinal, cerebral neurons especially hippocampus,
worn-out tissues throughout life. These are and peripheral nervous system. The scope of stem
immortal cells (unlike normal cells with a definite cell therapy is depicted in Fig. 79.2.
life span with programmed cell death—­apoptosis).
Stem cells have the ability to ­ self-replicate for A further attribute of resident stem cells is their
indefinite periods of time, and can differen- plasticity—capability of giving rise to a cell type of
tiate into different cell types in response to completely different tissue. For example, skin cells
­specific ­signals. In dermatology it has cosmetic can be transformed into neurons.1 This approach
applications to improve the skin, treatment of
­ will bypass the need of embryonic or fetal stem cells
burn ­injuries and scars. and play a major potential role in the ­treatment of
neurodegenerative disorders.
Totipotent cells are found only in early embryos,
which can differentiate into any of the over 200 cell
types in the body. Pluripotent cells are found in the Stroke Baldness
fetus, which can be obtained from medical termi- Traumatic brain injury
Blindness
nation of pregnancy and it is legal in India. The Learning defects
Alzheimer’s disease
placenta and umbilical cord are a rich source of Parkinson’s disease Deafness
multipotent stem cells. Menstrual blood is also a Amyotrophic lateral-
source of multipotent cells. Missing teeth sclerosis

Wound healing
Apart from pluripotent embryonic stem cells, which Myocardial
can differentiate into an endoderm—gastrointesti- Bone marrow infarction
nal (GI) tract, liver, lungs, ­mesoderm-hematopoietic transplantation
Muscular
(currently established)
and mesodermal/­ ectoderm—skin and central ner- dystrophy
vous system, (Fig. 79.1), there are r­esident stem Spinal cord injury
Diabetes
cells in adults in all tissues which are capable of
generating the cell type of the tissue in which they Osteoarthritis Multiple sites:
reside. The skin, mucosa and endometrium are Rheumatoid arthritis Cancers
constantly renewing systems due to resident stem
cells. Fig. 79.2: Potential uses of stem cells.

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 2670 IADVL TEXTBOOK OF DERMATOLOGY

STEM CELL THERAPY FOR INTRACTABLE Generation of new elastic fibers was evident
SKIN DISEASE by both special stains and antibodies to human
elastin and stimulated closure of full thickness
Bone marrow provides fibroblast-like cells in the
wounds. Tracking of green fluorescent protein
dermis and keratinocytes in the epidermis. Both
(GFP) showed GFP in blood vessels.
embryonic and postnatal transplantation of bone
marrow cells in mouse models of epidermolysis
Graft Versus Host Disease
bullosa (EB), a heritable blistering skin disease
due to a genetic mutation of cutaneous basement Dermatologic manifestations of graft versus host
membrane components, promote skin wound heal- disease (GVHD) have been reviewed by Scheinfeld
ing and correct the intrinsic basement membrane et al.7 MSCs can be used for the treatment of
defect. The source of epithelial progenitor cells in therapy—resistant GVHD. Factors involved in
­
bone marrow was the nonhematopoietic, platelet- GVHD are shown in Fig. 79.3.
derived growth factor receptor α (PDGFRα) posi-
tive mesenchymal stem cell (MSC) population.2

Prospective cell-based therapies for EB have been Effector cells

discussed by Uitto.3 Heritable forms of EB are char- (Donor < T-cells > Host)
acterized by chronic, lifelong blistering and ero-
sions at the cutaneous basement membrane zone. Cytokines
Autologous Allogeneic
Wong et al4 demonstrated the feasibility of direct dysrecognition (IL-1, IL-2, TNF, IFN) recognition
intradermal injection of allogeneic fibroblasts in
the lesional skin of patients with recessive dys-
trophic EB, with improvement in skin fragility. Host target Histocompatibility
antigen upregulated
It is considered more difficult to restore struc- (Skin, GUT, liver, etc.)
tural proteins than restore secretory enzymes. Tissue injury
EB is caused by defects in keratinocyte structural (ChemoTx, GVHD
proteins (Collagen 17). Both hemopoietic and infection, disease)
MSCs from bone marrow have the potential to
Fig. 79.3: Mechanism of development of GVHD.
produce Col 17. Furthermore, human cord blood
has CD34+ cells and can also differentiate into
keratinocytes and express human skin compo-
nent protein.5 Dermatologic manifestations are an important
aspect of (GVHD), and dermatologists are ­crucial
Wound Healing members of the treatment team. Acute GVHD
The nonhematopoietic component of bone mar- occurs within the first 100 days of t­ ransplantation,
row includes multipotent MSCs capable of differ- with the triad of dermatitis, enteritis, and h
­ epatitis.
entiating into fat, bone, muscle, cartilage, and Chronic GVHD develops after 100 days and
endothelium. consists of an autoimmune syndrome i­nvolving
­
the skin and multiple organs. Evidence of liver
Human MSCs are CD29+, CD44+, CD105+, and/or GI tract GVHD without skin involvement
CD166+, CD34-, CD45-. Autologous bone marrow- is rare. A skin manifestation of chronic GVHD is
derived cultured MSCs have been delivered into a lichen planus-like eruption or scleroderma, which
fibrin polymer spray system with a double barrel present therapeutic challenges.
syringe, into patients with acute wounds from skin
cancer surgery, and in patients with chronic, long- Staging and scoring system for skin involvement
standing, nonhealing lower limb wounds.6 Cells in acute GVHD is as follows:
were grown in vitro under conditions favoring the Stage 1 involvement of <25% of body surface
multiplication of MSCs. The cultured autologous
Stage 2 involvement of 25%–50% of body
MSCs were applied up to four times to wounds.
surface
Both fibrinogen (containing the MSCs) and throm-
bin were diluted to optimally deliver a polymerized Stage 3 involvement of 50%–100%
gel that immediately adhered to the wound without (erythroderma)
run-off and yet allowing the MSCs to remain via-
Stage 4 vesicles and bullae.
ble and migrate from the gel. Sequential adjacent
sections biopsy specimen showed elongated spin- MSCs have been used for the treatment of
dle cells, which immunostained for MSC markers. ­therapy—resistant GVHD.

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 CHAPTER 79: STEM CELL THERAPY 2671

SOMATIC CELL NUCLEAR TRANSFER (SCNT) stem cell therapy without the risk of immune
rejection. During SCNT, patient-specific donor cell
Human embryonic stem cells (hES) are a promis-
is fused into an enucleated donor oocyte to pro-
ing source for transplantation to replace diseased
duce blastocyst.
or damaged tissue, but their differentiated progeny
expresses human leukocyte antigens (HLA) that
Chris Mason,10 Director of London Regenerative
will probably cause graft rejection. Taylor et al8
Medicine Network in United Kingdom has esti-
have estimated that a bank of 150 consecutive
mated that more than 323,000 patients worldwide
blood group compatible donors, 100 consecutive
have received cell-based therapies, and has pre-
blood group donors provided a full match at HLA-A,
dicted that the market for stem cell and regenera-
HLA-B, and HLA DR match for approximately 85%.
tive therapy will rival drugs and medical devices.
A new technique involving reprogramming of adult
There are a handful of products in the market,
skin cells to induce pluripotent stem cells (iPS)
including a synthetic skin.
has become feasible.9 Amazing things like bone
regrowth, formation of teeth, retinal repair, cure
of deafness, skin replacement have been dem-
CONCLUSION
onstrated in animal models of iPS. Four factors
(OCT4, SOX2, NANO6, and LIN28) are sufficient Stem cells have proven to be of significant benefit
to reprogram human somatic cells to pluripotent in the management of chronic wounds, GVHD and
stem cells exhibiting the essential characteristics EB. Varieties of products containing stem cells are
of embryonic stem cells. being marketed of late for androgenetic alopecia,
facial rejuvenation and other indications. There is
SCNT is an approach to create autologous plu- no evidence as yet for the therapeutic effect of
ripotent stem cell lines, to enable patient-specific these products.

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