Stem Cell Therapy for Vascular Diseases State of the

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vi Preface

Belo Horizonte, Brazil Tulio Pinho Navarro, MD, PhD

Belo Horizonte, Brazil Lara Lellis Navarro Minchillo Lopes, MD
New Haven, CT, USA Alan Dardik, MD, PhD
Contents

1 Introduction to Stem Cell Therapy and Its Application

in Vascular Diseases ��������������������������������������������������������������������������������    1
Lara Lellis Navarro Minchillo Lopes, Tulio Pinho Navarro,
and Alan Dardik
2 Types and Origin of Stem Cells��������������������������������������������������������������   33
Lucíola da Silva Barcelos, Pollyana Ribeiro Castro, Elisabeth
Tamara Straessler, and Nicolle Kränkel
3 Stem Cell Delivery Techniques for Stroke and Peripheral
Artery Disease������������������������������������������������������������������������������������������   69
Shin-Rong Lee, Arash Fereydooni, and Alan Dardik
4 The Ethical Challenges of Stem Cell Therapy
in Vascular Disorders������������������������������������������������������������������������������ 105
Ramesh K. Batra
5 Bone Marrow-Derived Cells: From the Laboratory
to the Clinic���������������������������������������������������������������������������������������������� 115
Justin R. King, Jie Xie, and Michael P. Murphy
6 Angiogenesis: Perspectives from Therapeutic Angiogenesis���������������� 129
Monique Bethel, Vishal Arora, and Brian H. Annex
7 Stem Cell Therapy for Diabetic Foot Ulcers������������������������������������������ 155
Hallie J. Quiroz, Zhao-Jun Liu, and Omaida C. Velazquez
8 Venous Foot and Leg Ulcers�������������������������������������������������������������������� 173
Edith Tzeng and Kathy Gonzalez
9 Induced Pluripotent Stem Cell-Derived Vascular
Smooth Muscle Cells for Vascular Regeneration���������������������������������� 199
Biraja C. Dash

vii
viii Contents

10 Mesenchymal Stem Cell and Hematopoietic Stem

Cell Transplantation for Vasculitis �������������������������������������������������������� 221
Lianming Liao and Yongquan Gu
11 Mesenchymal Stem Cell and Endothelial Progenitor
Cell Transplantation for Buerger’s Disease������������������������������������������ 231
Lianming Liao and Yongquan Gu
12 Changing the Course of Peripheral Arterial Disease
Using Adult Stem Progenitor Cells�������������������������������������������������������� 245
Mark Niven, Galit Sivak, Shlomo Baytner, Roman Liberson,
Shlomo Bulvik, Yael Porat, Michael Frogel, Louis Shenkman,
Martin Grajower, Frank Veith, and Michael Belkin
13 Stem Cell Delivery for the Treatment of Arteriovenous
Fistula Failure������������������������������������������������������������������������������������������ 281
Akshaar N. Brahmbhatt and Sanjay Misra
14 Stem Cell Therapy to Improve Acute Myocardial
Infarction Remodeling���������������������������������������������������������������������������� 299
Jolanta Gorecka and Alan Dardik
15 Stem Cell Therapy for Stroke ���������������������������������������������������������������� 331
S. M. Robert and C. Matouk
16 Use of Stem Cells in the Treatment of Erectile Dysfunction���������������� 347
Benjamin Press and Stanton C. Honig
17 Stem Cell Therapy for Ophthalmic Vascular Disease�������������������������� 367
Caio Vinicius Regatieri, Augusto Vieira,
and Marcio Bittar Nehemy
18 Stem Cell Therapy Delivery in Liver Disease���������������������������������������� 385
John Langford and Gregory T. Tietjen
19 Stem Cell Therapy for Lymphedema ���������������������������������������������������� 407
Dylan McLaughlin, Angela Cheng, and Luke Brewster

Index�������������������������������������������������������������������������������������������������������������������� 421
Contributors

Brian H. Annex, MD Division of Cardiology and Department of Medicine,

Medical College of Georgia at Augusta University, Augusta, GA, USA
Vishal Arora, MD Division of Cardiology and Department of Medicine, Medical
College of Georgia at Augusta University, Augusta, GA, USA
Ramesh K. Batra, MBBS Yale School of Medicine, Yale University, Yale New
Haven Transplant Center, New Haven, CT, USA
Shlomo Baytner, MD Sanz Medical Center, Laniado Hospital, Netanya, Israel
Michael Belkin, MD Sanz Medical Center, Laniado Hospital, Netanya, Israel
Tel Aviv University, Tel Aviv, Israel
Monique Bethel, MD Division of Cardiology and Department of Medicine,
Medical College of Georgia at Augusta University, Augusta, GA, USA
Akshaar N. Brahmbhatt, MD Diagnostic Radiology - Department of Imaging
Sciences, University of Rochester, Rochester, NY, USA
Luke Brewster, MD, PhD Emory University, Department of Surgery, Vascular
Surgery and Endovascular Therapy, Atlanta, GA, USA
Atlanta VA Medical Center, Surgical and Research Services, Decatur, GA, USA
Georgia Institute of Technology, Institute for Bioengineering and Bioscience,
Atlanta, GA, USA
Shlomo Bulvik, MD Sanz Medical Center, Laniado Hospital, Netanya, Israel
Pollyana Ribeiro Castro, MD Physiology and Biophysics, Federal University of
Minas Gerais (UFMG), Belo Horizonte, Brazil
Angela Cheng, MD Emory University, Department of Surgery, Division of Plastic
and Reconstructive Surgery, Atlanta, GA, USA

ix
x Contributors

Lucíola da Silva Barcelos, PhD Physiology and Biophysics, Federal University

of Minas Gerais (UFMG), Belo Horizonte, Brazil
Alan Dardik, MD, PhD Vascular Biology and Therapeutics Program and the
Departments of Surgery and Cellular and Molecular Physiology, Yale University
School of Medicine, New Haven, CT, USA
Biraja C. Dash, PhD Department of Surgery, Division of Plastic Surgery, Yale
School of Medicine, Yale University, New Haven, CT, USA
Arash Fereydooni, MD Yale School of Medicine, New Haven, CT, USA
Michael Frogel, MD Cohen’s Children’s Medical Center, New Hyde Park, NY, USA
Kathy Gonzalez, MD Division of Vascular Surgery, University of Pittsburgh
Medical Center, Pittsburgh, PA, USA
Jolanta Gorecka, MD Vascular Biology and Therapeutics Program and the
Department of Surgery, Yale University School of Medicine, New Haven, CT, USA
Martin Grajower, MD Albert Einstein College of Medicine, Bronx, NY, USA
Yongquan Gu, MD Department of Vascular Surgery, Xuan Wu Hospital of Capital
Medical University, Beijing, China
Stanton C. Honig, MD Department of Urology, Yale School of Medicine, New
Haven, CT, USA
Justin R. King, MD Indiana Center for Vascular Biology and Medicine, Indiana
University School of Medicine, Indianapolis, IN, USA
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
Center for Regenerative Medicine, Richard L. Roudebush Veterans Administration
Medical Center, Indianapolis, IN, USA
Nicolle Kränkel, PhD Department of Cardiology, Campus Benjamin Franklin,
Charité – Universitätsmedizin Berlin, Berlin, Germany
John Langford, MD Department of Surgery, Yale University School of Medicine,
New Haven, CT, USA
Shin-Rong Lee, MD, PhD Yale School of Medicine, New Haven, CT, USA
Lianming Liao, MD, PhD Department of Laboratory Medicine, Fujian Medical
University Union Hospital, Fuzhou, China
Roman Liberson, MD, PhD Sanz Medical Center, Laniado Hospital,
Netanya, Israel
Zhao-Jun Liu, MD, PhD University of Miami Leonard M. Miller School of
Medicine, Miami, FL, USA
Contributors xi

C. Matouk, MD Department of Neurosurgery, Yale University School of Medicine,

New Haven, CT, USA
Dylan McLaughlin, MD Emory University, Department of Surgery, Vascular
Surgery and Endovascular Therapy, Atlanta, GA, USA
Lara Lellis Navarro Minchillo Lopes, MD Federal University of Minas Gerais,
Belo Horizonte, Minas Gerais, Brazil
Sanjay Misra, MD Department of Radiology, Mayo Clinic, Rochester, MN, USA
Michael P. Murphy, MD Indiana Center for Vascular Biology and Medicine,
Indiana University School of Medicine, Indianapolis, IN, USA
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
Center for Regenerative Medicine, Richard L. Roudebush Veterans Administration
Medical Center, Indianapolis, IN, USA
Tulio Pinho Navarro, MD, PhD Department of Surgery, Vascular Surgery Section,
Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Marcio Bittar Nehemy, MD, PhD Department of Ophthalmology, Federal
University of Minas Gerais, Belo Horizonte, MG, Brazil
Mark Niven, MD Sanz Medical Center, Laniado Hospital, Netanya, Israel
Yael Porat, PhD BioGenCell, Ltd., Laniado Hospital, Netanya, Israel
Benjamin Press, MD Yale School of Medicine, New Haven, CT, USA
Hallie J. Quiroz, MD University of Miami Leonard M. Miller School of Medicine,
Miami, FL, USA
Caio Vinicius Regatieri, MD, PhD Department of Ophthalmology, Federal
University of São Paulo, São Paulo, Brazil
Department of ophthalmology, Tufts Medical School, Boston, MA, USA
S. M. Robert, MD, PhD Department of Neurosurgery, Yale University School of
Medicine, New Haven, CT, USA
Louis Shenkman, MD Tel Aviv University, Tel Aviv, Israel
Galit Sivak, MD Rabin Medical center, Tel Aviv University, Tel Aviv, Israel
Elisabeth Tamara Straessler, MD Department of Cardiology, Campus Benjamin
Franklin, Charité – Universitätsmedizin Berlin, Berlin, Germany
Gregory T. Tietjen, PhD Department of Surgery, Yale University School of
Medicine, New Haven, CT, USA
xii Contributors

Department of Biomedical Engineering, Yale University, New Haven, CT, USA

Department of Surgery – Transplant Section, Yale School of Medicine, New
Haven, CT, USA
Edith Tzeng, MD VA Pittsburgh Healthcare System and University of Pittsburgh,
Pittsburgh, PA, USA
Division of Vascular Surgery, University of Pittsburgh Medical Center,
Pittsburgh, PA, USA
Frank Veith, MD NYU-Langone Medical Center, New York, NY, USA
The Cleveland Clinic, Cleveland, OH, USA
Omaida C. Velazquez, MD DeWitt Daughtry Department of Surgery, University
of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
Augusto Vieira, MD Department of Ophthalmology, Federal University of São
Paulo, São Paulo, Brazil
Jie Xie, MD, PhD Indiana Center for Vascular Biology and Medicine, Indiana
University School of Medicine, Indianapolis, IN, USA
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
Chapter 1
Introduction to Stem Cell Therapy and Its
Application in Vascular Diseases

Lara Lellis Navarro Minchillo Lopes, Tulio Pinho Navarro, and Alan Dardik

1.1 Introduction

1.1.1 Brief History of Stem Cells

Stem cells are undifferentiated cells capable of both self-renewal and differentiation
into various specialized cells [1]. Stem cell therapy is the therapeutic administration
of stem cells to repair or replace tissue function [2]. The term “stem cell” was pro-
posed by Alexander Maksimov in 1908 when developing “the unitarian theory of
hematopoiesis,” which proposed a common stem cell progenitor for all blood ele-
ments (Fig. 1.1) [3]. However, it was only in 1961 that the existence of murine cells
capable of self-renewal was proven by Till et al. while assessing radiation sensitivity
of bone marrow tissue [4].
In 1962, John Gurdon performed a classic experiment in frogs, in which he
replaced the immature cell nucleus in an egg cell with the nucleus from a mature
intestinal cell, resulting in a normal tadpole; this experiment showed that the DNA
of the mature cell had all the information needed to develop all cells in the organ-
ism, challenging the dogma that the specialized cell is irreversibly committed to its
fate [5].
In 1968, Friedenstein et al. reported the discovery of a human bone marrow cell
population with high proliferative potential and osteogenic activity in vivo [6]. In
the same year, Thomas et al. performed the first hematopoietic stem cell

L. L. N. M. Lopes
Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
T. P. Navarro (*)
Department of Surgery, Vascular Surgery Section, Federal University of Minas Gerais, Belo
Horizonte, Minas Gerais, Brazil
A. Dardik
Vascular Biology and Therapeutics Program and the Departments of Surgery and Cellular and
Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA

© Springer Nature Switzerland AG 2021 1

T. P. Navarro et al. (eds.), Stem Cell Therapy for Vascular Diseases,
https://doi.org/10.1007/978-3-030-56954-9_1
2 L. L. N. M. Lopes et al.

• The term “stem cell” is proposed by Maksimov.

1908

• Murine bone marrow stem cells are first isolated by Till et al.
1961

• Gurdon et al. demonstrates that mature cells’ nucleus keep information to develop all cell types.
1962

• Human bone marrow-derived stem cells are reported by Friedenstein et al.

1968

• Murine pluripotent stem cells are isolated by Evans and Kaufman.

1981

• Human embryonic stem cells are first isolated Thomson et al.

1998

• Murine somatic cells are induced to a pluripotent stem cell-like state by Takahashi et al.
2006

• Human somatic cells are induced to a stem cell-like state by Takahashi et al.
2007

• Gurdon and Yamanaka won the Nobel prize for their discoveries regarding cell reprogramming.
2012

Fig. 1.1 Timeline with the main events related to stem cell therapy history

transplantation for the treatment of leukemia [7]. Since then, theoretical implica-
tions of human stem cells and their potential clinical applications have been exten-
sively studied.
In 1981, Evans and Kaufman reported the isolation of murine pluripotent
embryonic stem cells, and this was followed by the report of Thomson et al., who
first isolated human embryonic stem cells in 1998 [8, 9]. Shinya Yamanaka and
Kazutoshi Takahashi identified several genes that kept cells immature while per-
forming research on murine embryonal stem cells in 2006. After that, they were
able to reprogram fibroblasts into immature stem cells; these resulting induced
pluripotent stem cells (iPSC) could develop into mature cell types such as fibro-
blasts, nerve cells, and gut cells, demonstrating that intact, mature cells could be
reprogrammed into pluripotent stem cells [10]. Later, in 2007, they reported
induction of human fibroblasts into a pluripotent state [11]. Takahashi’s experi-
ments reinforced the concept of using iPSC as a novel technological frontier in
stem cell therapy perspectives. In 2012, the Nobel Prize was awarded to John
B. Gurdon and Shinya Yamanaka in recognition of their findings showing that
mature, specialized cells could be reprogrammed, creating new opportunities to
study diseases and to develop new methods for diagnosis and treatment [12].

1.1.2  esenchymal Stem Cells vs Mesenchymal Stromal Cells

M
and Cell Markers

In 1991, the term “mesenchymal stem cell” (MSC) was proposed by Caplan et al. to
designate adult stem cells capable of differentiating into cells of mesodermal origin
[13]. However, as these cells showed limited capacity for self-renewal, thus they
1 Introduction to Stem Cell Therapy and Its Application in Vascular Diseases 3

failed to meet the criteria to be called stem cells. As such, the term “mesenchymal
stromal cell,” also abbreviated MSC, was then suggested as a more appropriate
designation to these regenerative cells [14].
In 2005, the International Society for Cell and Gene Therapy (ISCT) declared
that the terms “stem cell” and “stromal cell” were not equivalent [15]. Furthermore,
the term “stem cell” should be limited to a population of cells with demonstrable
self-renewal and differentiation capacities, while the term “stromal cell” referred to
cells with notable secretory, immunomodulatory, and homing features [16]. In addi-
tion, the ISCT provided the following minimal criteria to identify mesenchymal
stromal cells: being adherent to plastic; capable of differentiation into adipocyte,
chondrocyte, and osteoblast lineages; expression of CD73, CD90, and CD105; and
lack of expression of CD11b, CD14, CD19, CD34, CD45, CD79a, and HLA-DR
(Fig. 1.2).
Since then, stromal cell surface markers were shown to be plastic and influ-
enced by microenvironmental conditions and stem cell origin among other vari-
ables [16–18]. Therefore, there are no specific and unambiguous cell surface
markers to distinguish stem cells from stromal cells [16]. Ironically, since the
aforementioned ISCT statement, the interchangeable use of the terms “stromal”
and “stem” cells by the scientific community has spread. A search in the US
National Library of Medicine database (clinicaltrials.gov), performed in November
21, 2019, reported 1009 clinical trials related to the term “mesenchymal stem cell,”
while only 211 results were related to the term “mesenchymal stromal cell” [19].
Few authors have reported complete mesenchymal stromal cell characterization in
both preclinical and clinical publications, and the use of the term “mesenchymal
stem cell” remains controversial [16]. Hence, for the purpose of this chapter, the
abbreviation “MSC” will be employed to designate populations of regenerative
adult mesenchymal cells.
Most of the available data on clinical stem cell therapy relies on adult stem cells
and most frequently MSC. Moreover, the use of embryonal stem cells and induced

Adherence to plastic Marker expresssion Differentiation potential

MSC

MSC MSC

Positive Negative
CD73 CD11b
CD90 CD14
CD105 CD19
CD34
CD45
CD79a
HLA-DR Adipocyte Osteoblast Chondrocyte

Fig. 1.2 MSC criteria according to the International Society for Cell and Gene Therapy
4 L. L. N. M. Lopes et al.

pluripotent stem cells raises important ethical and safety concerns that impair the
use of these two cell types in clinical situations. Therefore, MSC are the main focus
of this chapter.

1.2 Differentiation Potential

Stem cells can be classified according to their differentiation potential into totipo-
tent, pluripotent, multipotent, and oligopotent cells. Totipotent stem cells are found
in the zygote and can differentiate in both embryonic and extraembryonic cells.
Pluripotent cells are also capable of giving rise to any type of embryonic cell, but
not to extraembryonic tissue. Multipotent cells give rise to multiple cells of the
same lineage whereas oligopotent stem cells have a narrower differentiation spec-
trum within a same lineage [1].

1.3 Stem Cell Types

Stem cells can be classified into embryonic stem cells (ESC), adult stromal cells,
and iPSC according to their origin (Fig. 1.3). The diverse characteristics, advan-
tages, and limitations of these groups (Fig. 1.4) lead to different clinical
applications.

1.3.1 Embryonic Stem Cells (ESC)

ESC are stem cells derived from the embryonic inner cell mass and possess unlimited
self-renewal capability as well as the ability to differentiate into any type of somatic
cell. Even though these cells have potential clinical application, clinical use of these
cells is scarce due to ethical conflicts involving the harvest and manipulation of
human embryos to obtain these cells. Additionally, embryonic stem cells’ unlimited

Fig. 1.3 Stem cell types

Stem cells

Adult Induced
Embryonic
pluripotent

Bone marrow Adipose tissue Peripheral blood Umbilical cord

 1

Stem Cell Type

Adult Stem Cells
Embryonic IPSC
BM-MSC PB-MSC UC-MSC ADSC
• Donor-specific therapy
• Lower malignancy risk • Future donor-specific
therapy • High differentiation
• Cell-lineage • Donor-specific therapy
• Lower malignancy risk potential (pluripotent)
committed (targeting • Lower malignancy risk
• Cell-lineage • Somatic-cell memory
• Donor-specific therapy differentiation) • Cell-lineage
committed (targeting (targeting
• Lower malignancy risk • No ethical conflict committed (targeting
differentiation) • High differentiation differentiation)
Advantages • Cell-lineage committed • Relatively disposable differentiation)
• Disposable tissue potential (pluripotent) • Donor-specific therapy
(targeting differentiation) tissue • No ethical conflict
• UC tissue harvesting • No ethical conflict
• No ethical conflict • Vein puncture has low • Disposable tissue
has low surgical risk • Disposable tissue
surgical risk • Liposuction has low
• Donor UCB banking • Low cell harvesting
• Simple cell harvesting surgical risk
storage procedure risk
protocol

• Cell lineage committed • Cell lineage

• Biopsy high surgical risk • Cell lineage committed committed • Increased malignancy
• Cell lineage • Increased malignancy
• Non-disposable tissue • Cell concentration and • lmmuno risk
committed risk
performance influenced incompatibility • Complex induction
Disadvantages • Low stem cell • Cell concentration and • Immuno
concentration by comorbities • Ethical conflict protocol
performance influenced incompatibility
• Cell concentration and • G-CSF administration • Low stem cell • Somatic-cell memory
by comorbities • Ethical conflicts
performance influenced by needed concentration (biased differentiation)
comorbities • Need of UCB banking
Introduction to Stem Cell Therapy and Its Application in Vascular Diseases

Fig. 1.4 Stem cell types, advantages and disadvantages [36]

5
6 L. L. N. M. Lopes et al.

differentiation potential lead to a higher risk of malignancy and requires immuno-

modulation as the use of allogeneic cells is mandatory for clinical therapy [20, 21].

1.3.2 Adult Stem Cells (ASC)

ASC are partially undifferentiated cells that can be found within nearly any organ or
tissue. Peripheral blood, umbilical cord, bone marrow, and adipose tissue are the
most common sources of such cells. Endometrium, amniotic fluid and membrane,
placenta, dental tissues, thymus, and spleen are unconventional sources of ASC. ASC
may be isolated from the same patient in whom the cell therapy will be applied
(donor-specific therapy) with no risk of immune rejection. There is no ethical con-
flict regarding the origin of these adult-derived cells or their isolation; however,
isolation protocols for ASC can be laborious, and a significant quantity of tissue is
frequently needed to obtain high stem cell counts [20].
ASC are lineage-committed multipotent cells, being able to differentiate
only into cells of the same germ layer [20]. This feature accounts for the lower
malignancy potential of ASC, and therefore these cells may be desirable to be
used in therapies that target specific cell differentiation, such as host tissue
replacement.

1.3.3 Induced Pluripotent Stem Cells (iPSC)

iPSC are stem cells generated through somatic cell reprogramming into an embry-
onic stem cell-like state, first reported in 2006 [10]. In theory, iPSC can be generated
from any somatic cell, and thus the use of these cells is emerging as an abundant and
accessible source of donor-specific stem cells free of ethical conflicts. These totipo-
tent cells demonstrate a broad differentiation potential, being capable of generating
any somatic or trophoblastic cell, but they also have a high malignant potential [22].
Because iPSC show advantages of both ASC, e.g., donor-specific therapy and
absence of ethical conflicts, and ESC, e.g., differentiation potential, this novel
source of stem cells is considered very promising. Nonetheless, strategies to
enhance the yield of cell induction into the stem cell-like state and simultaneously
control cell differentiation with absence of malignancy are still hurdles to be
overcome.

1.4 Stem Cell Origin

Stem cell therapy can be classified according to the cell origin as either autologous,
allogeneic, or xenogeneic transplantation (Fig. 1.5).
1 Introduction to Stem Cell Therapy and Its Application in Vascular Diseases 7

Stem cell origin

Autologous Allogeneic Xenotransplantation

• Healthy stem cell source • No ethical conflict

• lmmunoincompatibility
• No cell harvesting risk for the • Heathy stem cell source
• No ethical conflict
Advantages host patient • No cell harvesting risk for the
• No infection transmission risk
• Donor banking creation host patient
• Donor baking creation
• Lower stem cell concentration
• Relative
and limited healing potential
immunoincompatibility • High immunoincompatibility
Disadvantages • Cell harvestmg procedural
• Need of disease screening • Need of disease screening
risk
• Ethical conflict

Fig. 1.5 Stem cell origins, advantages, and disadvantages [36]

1.4.1 Autologous Transplantation

Autologous transplantation involves the administration of the recipient’s own cells,

typically using either ASC or iPSC. Autologous cells have the advantages of being
immunocompatible, having no risk of infectious disease transmission and involving
no ethical or legal issues. On the other hand, donor characteristics such as advanced
age, diabetes, obesity, and atherosclerosis exert negative impact on stem cell func-
tion, potentially decreasing the effectiveness of cell therapy [23–27]. Therefore,
past medical history and advanced patient age may be some of the limitations to the
use of autologous ASC for cell therapy.

1.4.2 Allogeneic Transplantation

Allogeneic cell transplantation is the exchange of cells between a donor and a recip-
ient of the same species. The use of cells isolated from a healthier or younger donor
could enhance the efficacy of stem cell therapy. However, allogeneic transplantation
has the drawbacks of lower immunocompatibility, risk of disease transmission, and
potential legal issues regarding exchange of biomaterials.
It has been hypothesized that allogeneic MSC are immunoprivileged. Nonetheless,
further research has shown that allogeneic MSC are not privileged, but demonstrate
diminished immunogenicity compared with other allogeneic cell types [28]. The
therapeutic implications of allogeneic MSC immunogenicity are controversial as
cell apoptosis is crucial for immunomodulatory effects but reduces therapeutic cell
longevity and engraftment [29].
Strict donor screening is needed to avoid disease transmission by allogeneic cell
therapy [2]. The use of cadaveric cells may be an alternative to enhance donor
availability and to avoid the risks associated to tissue harvesting therapeutic
cells [30].