eISSN 2005-5447

International Journal of Stem Cells Vol. 13, No. 1, 2020 https://doi.org/10.15283/ijsc19127

REVIEW ARTICLE

Hematopoietic Stem Cells and Their Roles in Tissue Regeneration

1 2
Ji Yoon Lee , Seok-Ho Hong

1
CHA Advanced Research Institute, CHA University, Seongnam, Korea
2
Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea

Hematopoietic stem cells (HSCs) are regarded as one of essential cell sources for treating regenerative diseases. Among
many stem cells, the feasibility of using adult-derived hematopoietic stem cells in therapeutic approaches is very diverse,
and is unarguably regarded as an important cell source in stem cell biology. So far, many investigators are exploring
HSCs and modified HSCs for use in clinical and basic science. In the present review, we briefly summarized HSCs
and their application in pathophysiologic conditions, including non-hematopoietic tissue regeneration as well as blood
disorders. HSCs and HSCs-derived progenitors are promising cell sources in regenerative medicine and their con-
tributions can be properly applied to treat pathophysiologic conditions. Among many adult stem cells, HSCs are a
powerful tool to treat patients with diseases such as hematologic malignancies and liver disease. Since HSCs can be
differentiated into diverse progenitors including endothelial progenitors, they may be useful for constructing strategies
for effective therapy.

Keywords: Hematopoietic stem cells, Stem cell therapy, Hematologic disorder, Liver disease

Introduction understanding the molecular mechanisms regulating the

self-renewal and cell fate determination of HSCs/progeni-
Hematopoietic stem cells (HSCs) are multipotent primi- tor cells is important for the development of clinical appli-
tive cells that can develop into all types of blood cells, in- cations based on disease type and severity. Only a small
cluding myeloid-lineage and lymphoid-lineage cells (1). population of HSCs is required to initiate the entire hem-
HSCs can be found in several organs, such as peripheral atopoietic process. Since Cheng et al. (2) first reported
blood (PB), bone marrow (BM), and umbilical cord blood that HSC quiescence is maintained by p21cip1/waf1 using
(UCB). All blood cell lineages are produced via functional p21−/− mice, numerous papers have found that long
maturation of a rare population of multipotent HSCs that term-hematopoietic stem cells (LT-HSC) quiescence and
can proliferate by self-renewal and differentiation. Thus, activation are regulated by the genetic and epigenetic reg-
ulation of key molecules as well as by microenvironmental
factors (3, 4). In addition to the attribute of self-renewal,
Received: October 12, 2019, Revised: November 18, 2019, a characteristic that distinguishes HSCs from other ma-
Accepted: December 1, 2019, Published online: December 31, 2019 ture cells is the ability to undergo specific and large-scale
Correspondence to Seok-Ho Hong differentiation into cells of various lineages. These find-
Department of Internal Medicine, School of Medicine, Kangwon
National University, 1 Gangwondaehak-gil, Chuncheon 24341, Korea
ings from a colony-forming unit (CFU) assay also revealed
Tel: +82-33-250-7819, Fax: +82-33-244-2367 HSC activity, and further measured the capacity of HSCs
E-mail: [email protected] to produce mature blood cells in humans following myelo-
This is an open-access article distributed under the terms of the Creative ablation. Similar with LT-HSC, numerous papers has
Commons Attribution Non-Commercial License (http://creativecommons.org/
licenses/by-nc/4.0/), which permits unrestricted non-commercial use, dis-
been studied the properties of short term HSC (ST-HSC)
tribution, and reproduction in any medium, provided the original work is and progenitors and addressed that HSC/progenitors can
properly cited. directly or indirectly contributes in regenerating tissues
Copyright ⓒ 2020 by the Korean Society for Stem Cell Research

1
 2 International Journal of Stem Cells 2020;13:1-12

and blood disorders. Based on these literatures, we de- tion including hormone and pericytes in BM (8). Similar
scribed the available sources of HSCs, aging HSCs, and to stem cells, progenitor cells in each step can also func-
plasticity of HSCs in scientific information and clinical tion as a strong cell source in regenerative medicine (Fig.
application of HSCs in blood disorders and liver defi- 1). Thus, understanding HSC/progenitor cells is im-
ciency. portant to apply these cells in regenerative medicine de-
pending on the disease type and severity. Thomas et al.
Definition of Hematopoietic Stem Cells (HSCs) (9, 10) reported that human BM cells infused into irradi-
ation and chemotherapy receiving patients, resulted in the
All lineage blood cells are produced by a rare pop- recovery of white blood cells and increased hemoglobin
ulation of multipotent HSC, which can proliferate by level. Two decades ago, existence HSC/progenitor cells in
self-renewal and differentiate to accomplish the functional vivo is proved by advanced technology such as retroviral
maturation. From HSC to mature cells, there are several skill and clinic application using HSC has been con-
intermediate progenitor cells (5). These cells can display tinuously developed with exclusive demand. Remarkably,
both functional multipotent and lineage-committed prop- Till and Mcculloch (1) showed a colony forming unit
erties simultaneously or separately prior to complete ma- (CFU) assay that can quantify HSC/progenitor cells; be-
turation. Blood is a highly regenerative tissue due to its cause HSC/primitive progenitor cells can repopulate
short life span, and BM supports the dynamic movement through self-renewal, regenerative HSCs can be assayed
of diverse cells to maintain homeostasis of blood cells. with clonal expansion to generate multipotent HSCs.
Approximately, one trillion cells are generated daily to Moreover, this method further motivated scientist to de-
compensate apoptotic cells in human BM, suggesting rap- velop ex vivo expansion for HSCs. Acquiring high number
id circulation of blood cells. HSC can be divided into of HSCs/progenitors is a critical issue in regenerative
LT-HSC, ST-HSC, and multipotent progenitor (MPP) in medicine in order to overcome the limitations of cell
terms of duration of repopulation (6). In normal physio- sources. Besides attributes of self-renewal, a distinguishing
logical conditions, rare HSC populations such as LT-HSC feature of HSC aggregation from other mature cells is its
can develop into all lineage blood cells in the BM. specific differentiation with huge numbers into various
However, HSC populations in the PB tend to be higher lineage cells. These findings from the CFU assay also re-
in myelosuppressive conditions caused by drug and gran- vealed LT-HSC activity, which further quantified HSC in
ulocyte colony-stimulating factor (G-CSF), and rapidly producing mature blood cells in patients with
migrate from the BM, suggesting different properties. myeloablation. Ultimately, we know that self-renewal pro-
HSC/progenitor cells in the PB are ST-HSC, which might liferation of HSCs and differentiation into committed cell
directly contribute to recovering damaged tissues, and lineages through intermediate stages including progenitors
these are regarded as optimal curative cell sources in re- are pivotal properties of HSCs. Because rare populations
generative medicine. Blood cells from HSCs are divided of HSC can lead the entire hematopoiesis, knowing the
into two lineages: lymphoid cells and myeloid cells (7). properties of HSC is very important to enhance ther-
The lymphoid branch consists of T, B, and natural killer apeutic effects in clinical application. Recently, aging is
(NK) cells, which are relevant to innate and adaptive im- emerging as an issue in HSC biology. Since Morrison et
mune cells. This process is known lymphopoiesis. Myeloid al. (11) mentioned homing and engraftment of HSCs
lineage cells include all blood cells except lymphoid cells. based on aging, many papers have demonstrated the rele-
There are several types of cells including monocytes from vance of aging by DNA damage in HSC and molecules
monoblasts, erythrocytes from erythroblasts, platelets from such as ATR gene and Cdc42 are pivotal to maintain phe-
megakaryocytes, and granulocytes, which consist of neu- notypes without HSC loss and back to rejuvenation (12).
trophils, eosinophils, and basophils, and are from myleo- The immune system is orchestrated in terms of coordina-
blasts. Lineage committed progenitor cells are specified tion of adaptive immune cells by lymphoid lineage cells
for cell fate and develop into mature cells through including T and B cells and innate immune cells by mye-
myelopoiesis. In myeloid lineage cells, committed myeloid loid cells. During aging, there is notable reduction in lym-
progenitors can be converted into mature types of myeloid phocytes, especially naïve T cells, which are apparent, as
cells. Lymphoid cells also have a similar process as the well as the accumulation and clonal expansion of memory
myeloid cells for generating progenitor cells and lympho- T cells (13). Meanwhile, myeloid lineage cells in BM seem
blast are from committed lymphoid progenitor cells. to be increased or persist at the same level in an age-de-
These blood cells are affected by dynamic niche composi- pendent manner, which leads to a proinflammatory envi-
 Ji Yoon Lee, Seok-Ho Hong: Hematopoietic Stem Cells and Their Roles in Tissue Regeneration 3

Fig. 1. Schematic illustration showed

hematopoiesis in adult BM. HSCs
have self-renewal activity and differ-
entiation capability into blood cell
lineages. LT-HSCs are quiescent and
sustained by arrested cell division in
endosteal niche, whereas ST-HSCs
are promptly differentiated into mye-
loid and lymphoid lineage cells in
vascular niche, and then lineage cells
exit into periphery.

ronment (14). Thus, identification and isolation of bona abolic checkpoint, in HSC aging, which suggested that mi-
fide HSCs with specific indicators should be demanded tochondria metabolism may play a role to govern juve-
prior to experiments to address HSCs by aging. Until now, nescence of HSCs (12). Although these evidence remain
identification of HSCs using CD markers has advanced unclear, pharmacological and metabolic interventions in
and the technique for isolation with high purity has been these pathways may be continuously exploited to restore
improved. function in aged HSCs. Epigenetic reprogramming as a
part of intrinsic regulation is one of the main factors in
Aging of Hematopoietic Stem Cells aging of HSCs. Although epigenetic abnormality is easily
detected, correlation between aged HSC and epigenetic
Research reports have consistently showed that under- aberrancy is unreadable due to the slow loss of normal
standing the properties of HSCs is very important for en- stem cell potential. Epigenetic regulation by TET2,
hancing their therapeutic effects in clinical applications. DNMT3, and EZH2 led to hematologic malignant trans-
Aging is relevant to the functional decline of normal formation, implying the faithful role of epigenetic control
HSCs as well as increased risk of hematologic malig- in the aging of HSCs (18). Epigenetic fidelity in a normal
nancies (15). Abnormal clonal hematopoiesis which fre- stem cell niche is required to maintain normal HSCs, be-
quently occurs in the HSCs of the elderly is caused by cause aging of HSCs is driven by a strong contribution
DNA mutation in specific loci and shortening telomerase of aged niche (19). Aged BM has two- to ten-fold HSCs
(16). Besides, there are several emerging intrinsic factors when compared to that of the young BM (11). Multiple
such as increased polarity, reactive oxygen species, and in- myeloma (MM) is a clonal plasma cell malignancy from
jured autophagy and mitochondria metabolism as ample BM failure by epigenetic defects (20). Thus, an epigenetic
evidence of aging of HSCs (17), which show the main fea- modulating agent such as decitabine is used to enhance
tures of aged HSCs compared to that of young HSCs. therapeutic efficacy in MM. Regardless of aberrant epi-
Especially, Mohrin et al. (17) showed the reversible con- genetic defects in the niche as well as autonomous HSCs,
tributing factor, deregulation of a UPR(mt)-mediated met- gene mutations may ultimately alter the epigenetic memo-
 4 International Journal of Stem Cells 2020;13:1-12

ry of HSCs, and then clonally expand with mutant epi- disease. Globally, 53% and 47% of HSCT is autologous
genetic memory leading to abnormal hematopoiesis. It and allogeneic, respectively, per year, and almost 68.8%
shows that modulation of epigenetic agents synergistically of total 854 patients (Acute myeloid leukemia (AML) 158,
enhances clinical drug responses and normalization of ab- acute lymphoblastic leukemia (ALL) 59, non-Hodgkin
normal mutation from aging status. The aging of HSCs lymphoma (NHL) 392, Hodgkin disease (HD) 245) are
depends on cellular changes, such as epigenetic factors, te- alive 10 years after autologous HSCT (24). Cell therapy
lomere and genomic damage, and molecular damage, in- using HSCs was first performed more than 60 years ago
cluding DNA damage, and finally resulting in dysfunc- (25). In humans, HSCs were identified and cultured in the
tional HSCs (15). Notably, the immune system is regu- 1980s (26). HSCT is one representative of many revolu-
lated via the coordination of adaptive immune cells by tionary solutions using HSCs, including cell and gene
lymphoid lineage cells, including T cells and B cells, and therapy. Among many other diseases, leukemia especially
of innate immune cells by myeloid cells. Aging leads to requires HSC therapy. AML is an aggressive malignancy
a reduction in lymphocytes, especially naïve T cells, and with high mortality; it has been considered the worst
the accumulation and clonal expansion of memory T cells blood cancer. For all AML types except M3, which is
(13). Meanwhile, myeloid lineage cells in BM appear to known as acute promyelocytic leukemia, HSCT is com-
increase or persist at the same level depending on age, monly conducted post-chemotherapy; the ultimate goal is
leading to a proinflammatory environment (14, 21). There the restoration of functional immune cells. HSCT pro-
are two models of HSC aging; one is a clonal alteration longs life and can be divided into two main methods: au-
model, in which all lymphoid cells can temporarily be tologous and allogeneic transplantation. Both methods of
converted into myeloid cells due to aging via a differ- HSCT are regarded as supportive care and are an estab-
entiation stage. The other is a population shift model, in lished therapy in many cases; in fact, HSCT has been in-
which myeloid-biased stem cells exclusively expand in old tegrated into the therapeutic strategy of most large, multi-
BM but not young BM, thus lymphoid-biased stem cell center, cooperative study group trials. Recently, studies on
populations are overwhelmingly decreased, resulting in an the effectiveness of autologous HSCT in older adults have
imbalance (17, 22). As previously mentioned, there is included patients harboring multiple types of hematologic
some debate regarding the properties of aged HSCs in hu- malignancies; for example, autologous HSCT has been
mans, and analysis of HSC characteristics during aging re- used as a therapeutic option among patients with both
mains inconclusive. Pang et al. (22) insisted that aged multiple myeloma (MM) and lymphoma (27). Among
HSCs do not engraft with increased homing abilities or hematologic malignancies, MM is the most common in-
differentiate into blood lineage cells with decreased effi- dication for autologous HSCT, and overall survival is pro-
ciency compared to young HSCs. In contrast, increased longed among patients treated with autologous HSCT
proliferative activity has been reported by Kuranda et al. compared to those treated with only conventional chemo-
(23) in aged HSCs compared to young HSCs. Because therapy. Of note, autologous HSCT during the first com-
both studies used different HSC markers to investigate the plete remission is not superior to the continuation of che-
characteristics of aged and young HSCs, there have been motherapy in any of the reviewed trials. Although the de-
inconsistencies after transplantation. Thus, the identi- bate is ongoing for AML, autologous transplantation in
fication and isolation of bona fide HSCs are required prior AML patients is still challenging due to the severe hetero-
to investigating aging HSCs, which can be achieved by ap- geneity of AML and graft versus host disease (GVHD).
plying recently developed advanced isolation techniques Meanwhile, allogeneic HSCT is more popular for many
that ensure high purity, and using improved HSC-specific types of diseases, including malignant and non-malignant
markers. disorders. For allogeneic HSCT, it is important to achieve
a high degree of human leukocyte antigen (HLA) match-
Hematopoietic Stem Cell Transplantation (HSCT) ing between the donor and recipient. Graft immune re-
for Blood Disorders jection and GVHD are remarkably decreased when well-
matched HSCs are transplanted. To achieve this, the HSC
HSCT involves the intravenous infusion of autologous donor should be investigated in diverse clinical aspects,
or allogeneic stem cells collected from BM, PB, and USB especially hematologic condition and HLA typing. Allo-
to reconstruct a functional hematopoietic system in pa- genic HSCT is used to treat the following disorders: leuke-
tients with blood disorders. This process is used to allow mia, including AML, ALL, chronic myeloid leukemia
a person to receive high-dose chemotherapy to treat a (CML), and chronic lymphocytic leukemia (CLL); myelo-
 Ji Yoon Lee, Seok-Ho Hong: Hematopoietic Stem Cells and Their Roles in Tissue Regeneration 5

proliferative disorders; MM, NHL; and anemia. Young direct cell contribution, such as paracrine effects, cell re-
CLL patients are able to undergo both autologous and al- cruitment, and microenvironmental modulation, can re-
logeneic HSCT. Both NHL and HD patients, who failed pair injured organs. In particular, liver cells, which are
to achieve complete remission by conventional therapy, from an endodermal lineage, rapidly acquire noticeable
are used to high dose chemotherapy with HSCT. This cellular functions and regenerative capacity. Because all
treatment can successfully induce complete remission in changes in the liver are elicited by highly conserved in-
relapsed patients (28). Anemia is a group of diseases in- trinsic signals and genetic factors, the activity of both
volving red blood cells. Among them, thalassemia major HSCs and oval progenitor cells in the liver is extremely
patients need blood transfusions; however, blood trans- relevant to developmental biology. Studies using animal
fusion is an insufficient treatment due to the presence of disease models are leading to the development of methods
the genetic problems associated with the disease (29). to derive hepatocyte and hepatic oval cells from diverse
HSCT treatment has undergone advancements over the stem/progenitor cell types (36). Among progenitor cells,
last two decades, and 80% disease-free survival has been endothelial progenitor cells (EPCs) represent progenitor
reported with allogeneic HSCT (30). Representative ther- cells that are derived from blood lineage cells; EPCs were
apeutic approaches, such as HSCT, have been improved; first reported by Asahara et al. (32). Later, EPCs were
furthermore, improved techniques, such as gene transfer studied by many investigators in regenerative medicine
with HSCT, could be used to treat a variety of diseases (37). Similar to HSCs, the ability to transdifferentiate
(31). EPCs into cells of other lineages has also been con-
tinuously debated (32). To enhance the use of stem/pro-
Contribution of HSCs/Progenitor Cells to genitor cells in therapeutic approaches, understanding
Regeneration of Non-Hematopoietic Cells how intrinsic regenerative capacities can be stimulated
will help facilitate the control of cellular plasticity in
HSCT is feasible in myeloablated and non-myeloablated stem/progenitor cells. Although the direct trans-
hosts, leading to a chimeric condition when allogeneic differentiation of HSCs or BM- derived progenitor cells
HSCT is carried out. In addition to using HSCT to induce to regenerative organs has been continuously debated and
hematopoietic cell reconstruction, cell therapy using BM- does not seem to happen in vivo, HSCs/progenitor cells
derived stem/progenitor cells has been continuously ap- are still considered important elements in injury repair in
plied in regenerative medicine. Additionally, tissue-specif- terms of disease severity and organ types (38-49). We have
ic stem/progenitor cells in hematopoietic and non-hema- briefly summarized the contribution by the plasticity of
topoietic tissues are also regarded as important ther- HSCs/progenitors to non-hematopoietic tissue re-
apeutic cell sources. BM-derived stem/progenitor cells are generation in Table 1.
able to differentiate into cells of other lineages in a proc-
ess called transdifferentiation, as well as differentiation HSCs in Liver Regeneration
(32). Many reports have shown that HSCs can trans-
differentiate into cells of other lineages, such as endothe- Liver regeneration is a fundamental response of the liv-
lial cells, cardiomyocytes, neural cells, and hepatocytes er to injury. Similar to other organs, it is well known that
(33, 34). These results seem to contradict the common as- local preexisting hepatic progenitor cells and circulating
sumptions of cell origins from the three germ layers and BM-derived progenitor cells are major contributors during
question whether HSCs are multipotent cells that can liver regeneration (50). All elements are orchestrated, and
transdifferentiate or whether they are more primitive then complete liver regeneration is accomplished. It has
functional cells. However, since the mid-2000s, refutations been shown that hepatocyte proliferation mainly contrib-
of the plasticity of HSCs are emerging in regenerative utes to liver regeneration and is regulated by various fac-
medicine fields, suggesting that there is only a limited tors and cytokines, such as hepatocyte growth factor, epi-
population of HSCs under physiological conditions (35). dermal growth factor, and interleukin-6 (51). When hep-
Stem/progenitor cells are needed to regenerate organs, and atocytes cannot function due to factors such as toxins and
interest in stem/progenitor cells has been fueled by a seri- carcinogens, hepatic progenitor cells can be found in the
ous need for lineage-specific progenitor cells for the treat- injured liver. Liver progenitors/oval cells are very small
ment of diseases. Additionally, despite the rarity of stem/ and contain little cytoplasm and oval nuclei. Although
progenitor cells in regenerated organs, it is now believed preexisting mature hepatocytes are the quickest and most
that diverse effects from stem/progenitor cells other than efficient cell sources for liver repair, their renewal ca-
 6 International Journal of Stem Cells 2020;13:1-12

Table 1. Contribution of HSCs/progenitor cells in regeneration of non-hematopoietic cells

Source of stem cells Differentiation of HSCs/progenitors Year Reference
1 BM-hematopoietic cells Microglia/Macroglia 1997 (38)
2 BM-myogenic progenitors Muscle cells 1998 (39)
3 BM-Stem cells Endothelial precursors 1999 (40)
4 BM-Stem cells Hepatic oval cells 1999 (41)
5 BM-Stem cells Neuronal cells 2000 (42)
6 BM-Stem cells Hepatocytes 2000 (43)
7 Hematopoietic stem cells hepatocytes 2000 (34)
8 BM-Stem cells Cardiac muscle 2001 (44)
9 BM-side population cells Cardiac muscle, endothelium 2001 (45)
10 PB-stem cells Hepatocytes/epithelial cells 2002 (46)
11 BM-Stem cells Cardiac muscle 2005 (47)
12 BM-Stem cells Lymphatic endothelial progenitors 2010 (48)
13 Corticalbone-derived stemcell Myocytes/vascular cells 2013 (49)

pacity is exhausted and impaired under some pathological press the Thy-1 HSC marker when hepatic injury is in-
conditions. Thus, hepatic stem/progenitor cells, rather duced by 2-acetylaminofluorene. This finding indicates
than mature hepatocytes, actively proliferate and differ- that the Thy-1＋ oval cell population could be used to
entiate into hepatocytes. This phenomenon occurs in both study hepatic oval cells. Theise et al. (55) reported that
mice and humans (52). Clinically, liver transplantation is BM cells can transdifferentiate into hepatocytes in irradi-
the only available therapy for terminal liver failure. ated mice and humans. Based on this concept, Lagasse et
However, the greatest impediment is finding a suitable al. (34) tried to isolate purified HSCs and differentiate
HLA-matched donor. Therefore, there has been a major them into hepatocytes, resulting in a high proportion of
effort to develop alternative methods or sources to im- bone marrow stem cell (BMSC)-derived hepatocytes fol-
prove liver regeneration. Increasing evidence suggests that lowing strong positive HSC selection. Several studies have
BM-derived stem/progenitor cells can differentiate into suggested that hepatic stem/progenitor cells possess the
hepatocytes, thus resulting in the accumulation of hep- phenotype of a side population of blood cells that has the
atocytes (53). Starzl (54) performed the first liver trans- ability to efflux Hoechst 33342. This side population of
plantation and attempted five more transplantations in cells among liver cells is similar to hematopoietic lineage
1963. After that, the mixed chimeric status of blood cells cells and expresses the CD34 marker. When hepatic stem
in the liver after transplantation was reported by cells are activated, BCRP1 (ABCG2) mRNA usually in-
Taniguchi et al. in 1996 (53). Hepatocytes can be found creases in liver tissue. Because BCRP1 is one of the deter-
in the transplanted livers of animals and humans, and minants of the side population, its detection indicates an
transplantation of reduced-size liver grafts accelerates the increase in hepatic stem cells with the side population
recruitment and regeneration of these cells (50). This pa- phenotype (56). Most experiments that address the con-
per showed that BM-derived CD34＋ cells can be directly tribution of HSC-derived cells in liver regeneration use a
incorporated into newly regenerated liver following liver mouse injury model and have shown that liver regene-
transplantation in humans, suggesting the transdifferent- ration is caused by the clonal expansion of multipotent
iation of BM-derived stem/progenitor cells into hepato- HSCs (33, 34, 50). Krause et al. (33) reported that
cytes. Although liver cells are derived from the endoderm non-hepatic adult stem cells can differentiate into hep-
and blood cells are derived from the mesoderm, the con- atocytes in humans. In addition, the differentiation ca-
cept of transdifferentiation is emerging in liver regene- pacity of human HSCs into cells of other lineages, includ-
ration fields. In mice, the adult liver consists of c-kit＋ ing skin, gut, and liver cells, has been reported (57).
Sca-1＋Linlow/− cells, which are defined as HSCs, and these Human biopsy liver samples have shown that circulating
cells can form hematopoietic colonies in vivo and in vitro blood stem cells differentiate into mature hepatocytes and
(53), which shows the intimate relationship between hem- epithelial cells via sex-mismatched transplantation. As
atopoietic cells and hepatocytes. Although hepatic lineage mentioned previously, all extrahepatic stem/progenitor
cells are totally different from hematopoietic lineage cells, cells contribute to liver regeneration. However, the low ef-
Petersen et al. also showed that hepatic oval cells can ex- ficiency (less than 0.01%) of extrahepatic stem/progenitor
 Ji Yoon Lee, Seok-Ho Hong: Hematopoietic Stem Cells and Their Roles in Tissue Regeneration 7

cell contribution post HSCT has been a matter of debate. the different levels of contribution, BM-derived HSCs/pro-
Most scientists think that extrahepatic cells, such as genitor cells might be a suitable tool for addressing some
BM-derived HSCs/progenitor cells, fuse with host hep- liver diseases, such as metabolic defects, via fusion-medi-
atocytes rather than transdifferentiate, which requires con- ated additive gene transfer. Additionally, because de novo
firmation by cytogenetic analysis (58). However, while it regenerated liver is very important for transplant survival
is relatively easy to obtain samples from mouse models, in humans, the contribution of BM-derived HSCs is also
acquiring a transplanted liver sample from humans is very considered important in clinical practice. Many clinical
difficult. Nevertheless, all evidence suggests that cell fu- studies have suggested the implementation of HSC and
sion occurs rather than BM-derived HSCs/progenitor cell hepatocyte transplantation (59). Clinical approaches using
transdifferentiation. However, Lee et al. (50) clearly BM-derived cells, including mononuclear cells (MNCs),
showed transdifferentiation of BM-derived CD34＋ CD34＋ stem cells, and mesenchymal stem/stromal cells
stem/progenitor cells in human liver transplants. Despite (MSCs), have been attempted for the treatment of liver

Table 2. Clinical trials on stem cell therapy in liver disease

Source of stem cells No. of patients Year Reference
1 BM-MNCs 9 2006 (59)
2 PB-MNCs, G-CSF 2 2006 (60)
3 BM-MSCs, G-CSF Active Treatment: 8 (5 male) 2006 (61)
4 CD34＋ cells 5 2006 (62)
5 CD34＋ cells 4 2007 (63)
6 BM-MSCs 10 2007 (64)
7 PB-monocytes, G-CSF 2 2007 (65)
8 CD34＋ cells 4 2008 (66)
9 CD34＋ cells 5 2008 (67)
10 PB-MSCs, G-CSF 40 2008 (68)
11 CD34＋ cells 9 2008 (69)
12 CD34＋, CD133＋ HSCs Active Treatment: 90 (78 male) 2010 (70)
13 BM-MNCs 10 2010 (71)
14 BM-MNCs 15 2010 (72)
15 hHPCs Active Treatment: 4 2010 (73)
16 BM-MNCs, HSCs 6 2011 (74)
17 BM-MNCs 5 2011 (75)
18 BM-MNCs (BM-derived hepatocytes) 20 2011 (76)
19 CD34＋ cells, G-CSF 23 2012 (77)
20 BM-MSCs, G-CSF 28 2013 (78)
21 BM CD133＋ cells 16 2015 (79)
22 BM CD134＋ cells, G-CSF 81 2015 (80)
23 PB CD34＋ cells 22 2015 (81)
24 BM CD133＋ cells, MNCs 12 2016 (82)
25 PB monocytes 9 2017 (83)
Source of stem cells Clinicaltrials.gov identifier Year Phase
26 Autologous expanded CD34＋ HSCs NCT00655707 2008∼2015 Phase2
27 Autologous BM cells NCT02943707 2016∼2020 Phase2
28 Autologous BM-derived CD133 stem cells NCT01120925 2010∼2014 Phase2
29 BM cells NCT01412593 2011∼2013 Phase2
30 Autologous BM-derived CD133 stem cells NCT00713934 2008∼2010 Phase1
31 Adult stem cells NCT00147034 2005∼2016 Phase1
32 Autologous BM-derived CD133 stem cells NCT01025622 2009∼2010 Phase1
33 Allogenic BMSCs NCT01221454 2010 Phase2
34 Allogenic BMSCs NCT01223664 2010 Phase2
35 Human BMSCs NCT01724697 2012 Phase1
36 Autologous BMSCs NCT02943707 2016 Phase2
 8 International Journal of Stem Cells 2020;13:1-12

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