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14 Cell Therapies: New Frontier fortheManagement ofDiabetic Foot Ulceration
https://t.me/med1917
265
Fig. 14.5 3D skin equivalent
tissue model for wound
healing. Patient-derived cells
and adult or iPSCs can be
used to create an invitro
human tissue model of wound
healing. HSE tissue wound
model is developed through
the following sequential steps:
(a) HSE tissue is fully
developed. (b) A fullthickness wound is made in
the tissue using a biopsy
punch. (c) Wounded tissue is
placed on second dermal
layer. (d) Keratinocytes from
wounded tissue migrate
across the wound bed. (e)
Wound is fully
re-epithelialized and healed.
Overhead view is on the left.
This tissue model can be used
to test how stem cells can
stimulate wound healing
aa
b
c
c
e
e
b
d
It has been shown that the tissue microenvironment plays
a critical role in the epigenetic regulation of gene expression
in 3D tissues [201]. This claries that the impact of epigenetic alterations of gene expression on human disease pathways can be modeled in a complex 3D tissue context. It is
clear that “surrogate” 3D tissues will elucidate mechanisms
through which epigenetic control of gene expression and the
3D microenvironment drive the development of DFUs. This
will enable the use of epigenetic targets in diabetic cells to be
used as readouts of improved DFU wound healing response.
In the future, it will be necessary to scale these 3D tissues
the use of iPSCs can be compared as they are developed as
a future paradigm for the treatment of DFUs using a single,
self- replenishing stem cell source that can differentiate into
multiple cell types needed for DFU repair. Modication of
both adult and pluripotent stem cells with CRISPR/Cas9
gene editing is another new tool available for improving
wound repair of DFUs. To test the efcacy and safety of
these novel therapies, 3D human skin equivalents and
organs-on-chips will provide effective, customizable models that will allow efcient optimization of these new thera-
peutic approaches.
to high throughput formats to enable the rapid, global screening of tissue responses that mimic DFUs. Development and
optimization of DFU-specic, customized 3D tissue models
References
will be prepared with genetic modications, for example,
CRISPR/Cas9, that will enhance the screening of stem cell
therapies before they are tested in humans. The DFU research
community would benet greatly by the development of
invitro tools and resources to provide disease-specic and
pathway-specic, skin-like tissues that mimic the essential
features of DFUs.
Pre-clinical animal and human studies offer clear evidence that stem cell therapies offer an effective approach
for treating DFUs. Studies demonstrating the potential of
using adult stem cell sources, including MSCs, HSCs,
EPCs, MNCs, and ASCs, now provide a baseline to which
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Role ofExtracellular Vesicles, Modified
https://t.me/med1917
mRNA, miRNA, andsiRNA inDiabetic
Lower Extremity Complications
GeorgiosTheocharidis andJennyLi
15
Abstract
Diabetic foot ulcers (DFUs) are a global health concern
that requires urgent attention, given the projected increase
in the diabetic population. These non-healing ulcers often
become infected and can ultimately result in amputation.
In an effort to enhance healing outcomes, gene therapy
has emerged as a promising alternative to conventional
treatments such as bioengineered materials/tissues or
growth factors. RNA-based therapeutic approaches,
including siRNA, miRNA, and mRNA, have shown
remarkable potential in addressing chronic wounds in
various preclinical models and human clinical trials. To
optimize the delivery of target RNA, researchers have primarily focused on nucleic acid delivery nano-carriers
(such as extracellular vesicles and lipid nanoparticles)
and RNA modication techniques (including chemically
modied nucleobases and ligand conjugation). In this
chapter, our focus is on the recent advancements in the
development of extracellular vesicles and RNA-based
therapeutics, as well as ongoing research related to genes
that play a crucial role in the processes of chronic wound
healing.
Extracellular Vesicles andWound Healing
The skin is the body’s largest organ and acts as a barrier to
protect against environmental harm. However, wounds
resulting from acute and chronic injuries such as trauma,
burns, and diseases can be difcult to heal and lead to physical and psychological suffering for patients. These wounds
also impose a heavy economic burden on society. Recent
G. Theocharidis (*) · J. Li
Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu,
MD, Center for Regenerative Therapeutics, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, MA, USA
e-mail: gtheocha@bidmc.harvard.edu; zli5@bidmc.harvard.edu
research has shown that the use of extracellular vesicles
(EVs) and natural nano-sized particles derived from cells,
including exosomes and microvesicles, can promote wound
healing. EVs are primarily categorized into two types according to their size: exosomes (30–100nm) and microvesicles
(MVs) (50–1000nm) [1]. EVs deliver growth factors, cytokines, and other molecules including nucleic acids and lipids
that can mediate a multitude of biological events, such as cell
proliferation, anti-inammation, angiogenesis, and reepithelization, thereby facilitating wound repair. EVs are
advantageous because of their biocompatibility, low immunogenicity, minimal toxicity, and cost-effectiveness, making
them promising therapeutic nanoparticles for applications in
regenerative medicine.
While natural EVs hold promise for wound healing, their
low concentration, short half-life, rapid degradation, and
low-efciency payload substantially hinder their clinical
applications. To overcome these limitations, engineered EVs
have emerged as a new type of EV-based nanotherapeutics
[2]. Various engineering methods have been explored to
enhance the therapeutic potential of EVs in wound repair,
including membrane modication, cargo incorporation, and
combination with other nanomaterials. These approaches
show promising prospects.
Exosomes and MVs are two types of EVs with distinct
biogenesis processes [3, 4]. Exosomes originate from the
endosomal system and are secreted via fusion of the plasma
membrane with multivesicular bodies (MVBs) containing
intraluminal vesicles (ILVs), while MVs are released via outward budding of the cell membrane. Despite the different
cellular locations, their biogenesis mechanisms share some
similarities. Exosome biogenesis involves several stages:
inward budding of the plasma membrane to form early endosomes, which mature into MVBs containing ILVs. MVBs
then either degrade via lysosomal fusion or release exosomes
when transported to the cell membrane and fused with it. The
process of exosome release involves Rab and SNARE families. Exosomes are formed via ESCRT-dependent or -independent mechanisms.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
A. Veves et al. (eds.), The Diabetic Foot, Contemporary Diabetes, https://doi.org/10.1007/978-3-031-55715-6_15
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G. Theocharidis and J. Li
EVs are enriched with various biologically active cargos
during their biogenesis, which vary according to parental cell
type, physiological conditions, and the biogenesis pathway.
Common EV contents include nucleic acids, proteins, and lipids, with specic examples such as mRNA, miRNA, HSP70,
CD9, and phosphatidylserine [5]. Upon arrival at recipient
cells, EVs release their cargos to exert diverse biological functions. The uptake of EVs varies depending on the donor and
recipient cells. Direct fusion of the EV membrane with the cell
membrane involves protein families, such as SNAREs, Rab
proteins, and SM-proteins [6]. Endocytosis is an additional
essential mechanism for EV uptake, entailing clathrin-mediated pathways, caveolin-dependent uptake, macropinocytosis,
phagocytosis, and lipid raft-associated internalization [7, 8].
Cell adhesion molecules (e.g., PS receptors, lectins, glycans,
and integrins) localized on EVs allow them to bind and be
taken up by recipient cells via ligand-receptor interactions,
enabling cell-to-cell communication via secreted EVs [9].
Wound healing is a multifaceted process that involves a
series of tightly regulated events, including blood clot formation, re-epithelialization, granulation tissue deposition, and
neovascularization. This biological process consists of four
distinct phases: hemostasis, inammation, proliferation, and
remodeling, which are complex and overlapping [10].
The hemostasis phase initiates wound healing, where
blood vessels constrict in response to injury and blood clots
form to prevent blood loss and safeguard the wound against
pathogens. Platelets release cytokines, hormones, and chemokines to activate the healing stages [11]. During the
inammation phase, various immune cells, either tissueresident or inltrating to the injury site, are activated and
remove pathogens, apoptotic cells, and cellular debris
involved in wound healing. Neutrophils eliminate pathogens
and damaged cells by phagocytosis and secretion of proteases. Macrophages derived from systemically recruited
monocytes clear apoptotic bodies and cellular debris, and
secrete growth factors to stimulate cell proliferation [12, 13].
The proliferation phase is marked by re-epithelialization
of the injured tissue as keratinocytes migrate to close the gap
and broblasts proliferate to support the new tissue formation in the dermis [14]. Angiogenesis is stimulated by an
increase in growth factors such as FGF and VEGF, while
broblasts produce a new extracellular matrix (ECM) by
secreting type III collagen, which aids in wound closure
[15]. Finally, type III collagen is gradually substituted with
type I collagen during the remodeling phase, which involves
ECM structure adjustment and collagen breakdown, resulting in reduced wound size and thickness [16].
Role ofMSC-Derived EVs inWound Healing
Mesenchymal stem cells (MSCs) are pluripotent cells
derived from various tissues and organs that can differentiate
into various cell types. MSC-derived EVs contain transcription factors, anti-inammatory and growth factors that aid in
tissue regeneration. These EVs play a crucial role in all
stages of wound healing, making them a potential therapeutic agent [17].
MSC-Derived EVs Modulate Inammation
While inammation is necessary for wound healing, excessive
inammation can be harmful. Macrophages play a crucial role
in inammation with broadly dened two types: pro-inammatory M1 and pro-reparative/inammation- resolving M2.
MSC-derived EVs can polarize macrophages toward M2 to
achieve anti-inammatory effects [18]. This polarization is
mediated by Let-7b from MSC-derived EVs through inhibiting TLR4 signaling [19]. Additionally, MSC- derived EVs
regulate cytokine expression to attenuate inammation. These
EVs inhibit pro-inammatory enzymes such as iNOS and
COX-2 and downregulate cytokines and chemokines like
TNF-α, IL-1β, and MCP-1 while upregulating pro-healing
cytokines such as IL-10 to accelerate wound healing [20, 21].
Furthermore, MSC-derived exosomes can facilitate the conversion of activated T lymphocytes to the T-regulatory phenotype to subsequently promote wound healing by decreasing
the production of interferon-γ and enrichment of M1 polarized
macrophages [22]. In addition, miRNAs from MSC-EVs
exhibit immunomodulatory effects during this wound healing
stage. Elevated levels of miR-21 and miR−181c are implicated in regulation of immune responses [23].
Modulation ofProliferation
MSC-derived EVs can promote angiogenesis and enhance
the proliferative phase of wound healing. miR-125a and
miR-31 in human adipose-derived stem cell (hADSC)derived exosomes can transfer to endothelial cells to block
angiogenic inhibitor DLL4, thus promoting the formation of
endothelial tip cells [24]. Exosomes from ADSCs also
upregulate the expression of growth factors and proliferative
markers to activate AKT and ERK signaling pathways and
promote angiogenesis [25]. Exosomes from EPCs and
human-induced pluripotent stem cell (hiPSC)-MSCs can
also enhance angiogenesis and collagen synthesis [26].
ADSC-Exos can enhance migration and proliferation of
broblasts through the synthesis of N-cadherin, Cyclin-1,
PCNA, and collagen types I and III [27]. Long non-coding
RNA MALAT1in ADSC-Exos and bone marrow stem cellderived CD63+ exosomes carrying external Wnt3a can also
promote wound healing [28, 29]. Human umbilical cordderived mesenchymal stem cells-Exos activate Wnt4/β- -
catenin and AKT signaling pathways to accelerate
re-epithelialization and promote skin regeneration [30].
Finally, hiPSC-MSC-Exos stimulate the secretion and of
type I and type III collagens and, elastin, therefore, promoting the proliferation and migration of human dermal broblasts and enhancing skin regeneration [26].
15 Role ofExtracellular Vesicles, Modied mRNA, miRNA, andsiRNA inDiabetic Lower Extremity Complications
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Modulation ofRemodeling
The impact of hypertrophic scarring on tissue and organ
appearance and function is a pressing issue for clinicians to
address during the tissue remodeling phase of wound healing
[31]. Emerging evidence suggests that EVs play a critical
role in wound healing by regulating matrix remodeling and
promoting the recruitment of wound-healing factors. For
example, ADSCs-EVs promote skin regeneration by
upregulating collagen I and III synthesis and downregulating
collagen expression to reduce scarring [32]. HUCMSCexosomes inhibit the TGF-β/SMAD2 signaling pathway,
preventing broblasts from becoming myobroblasts, while
the 14–3- 3ζ protein suppresses collagen deposition and
broblast expansion through regulation of the Hippo-YAP
pathway [33]. HiPSC-MSC-exosomes enhance collagen
maturation and reduce scar width by increasing the production of type I and III collagen and elastin [26]. Finally, high
doses of human aortic endothelial cells (hAEC)-derived EVs
can decrease extracellular matrix deposition by inducing
MMP-1 expression, resulting in scarless wound healing [34].
Collectively, these ndings indicate that MSC-EVs have signicant potential as a treatment to reduce scar formation during the remodeling phase.
have been found to be benecial in diabetic wound healing
as they stimulate multiple biological events such as reepithelialization, cell proliferation, collagen deposition, new
blood vessel creation, and inammation inhibition by activating the Akt/β-catenin pathway [38]. Fibroblast-derived
EVs (L929-EVs) have also been found to be effective in promoting wound healing by increasing the expression of
VEGF, enhancing collagen synthesis and maturation, and
inducing the formation of blood vessels and skin appendages
[39]. In addition, keratinocyte microvesicles (KC-MVs) play
an essential role in promoting wound healing by regulating
gene expression and activating multiple signaling pathways
in dermal broblasts. Furthermore, human KC-MV miR-21
enhances angiogenesis and activates the function of broblast [40, 41]. Human keratinocyte-derived EVs (HaCaT)
also have the ability to promote wound healing by stimulating the migration, proliferation, and activation of ERK1/2
and P38 of human keratinocytes and broblasts via the
MAPKinase pathway [42] and epidermal stem cell-derived
Exos have exhibited advantageous effects in accelerating
diabetic wound healing [43]. These studies demonstrate that
EVs derived from broblasts and keratinocytes have signicant potential in promoting wound healing and could represent a promising new approach to chronic wound therapy.
Macrophage-Derived EVs inWound Healing
Recent reports have demonstrated that macrophages and
their EVs contain different cytokines and miRNAs that have
a signicant role in reducing inammation through a paracrine mechanism with recipient cells [35]. Exosomes derived
from macrophages can markedly expedite the processes of
angiogenesis and re-epithelization, while also reducing the
levels of pro-inammatory cytokines (TNF-α and IL-6) to
enhance wound healing in diabetic patients [36]. Additionally,
macrophage-derived EVs are also associated with scar formation, where the lncRNA-ASLNCS5088 of M2 macrophage exosomes is transferred to broblasts to hinder the
function of miR-200c-3p. This results in increased expression of GLS and α-SMA, which regulate scar formation [37].
The results of these studies suggest that macrophage-derived
EVs could be a promising therapeutic approach to enhance
wound healing.
Fibroblast andKeratinocyte-Derived EVs
inWound Healing
EVs that are produced and secreted from stromal or epidermal cells play a crucial role in various biological processes
during wound healing such as ECM deposition, tissue
remodeling, and wound contraction. For example, autologous dermal broblasts (DF-Exos) released from exosomes
Endothelial Cell-Derived EVs inWound Healing
Endothelial cells secrete EVs (ED-EVs) that regulate diverse
biological activities such as monocyte adhesion, cell migration, and angiogenesis [44]. Plasma ED-EVs promote wound
healing by increasing microvascular density and collagen
deposition through the activation of the PI3K/Akt/mTOR
pathway [45]. Conversely, endothelial cell-derived EVs containing miR-106b-5p delay wound healing by reducing collagen production through the ERK1/2 pathway [46]. In
addition, HUVEC-derived EVs hamper wound healing by
reducing angiogenesis and collagen synthesis through
JMJD3 and RIPK3 inhibition [47]. In summary, endothelial
cell-derived EVs can serve as both therapeutic tools and
blockade targets for wound treatment applications.
Blood Cell-Derived EVs inWound Healing
Various different studies have indicated that EVs from blood
can assist with wound healing. Platelet-rich plasma (PRP)
has been applied extensively for the treatment of different
types of chronic wounds. PRP-derived exosomes activate
YAP to induce re-epithelialization and angiogenesis in
chronic wounds by regulating broblast and endothelial cell
proliferation and migration [48]. Additionally, PRP-derived
exosomes contain the mediator USP15, which promotes the
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