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The Modern Implication of Hematopoietic Stem Cell Research Toward Regenerative

Tissue and Its Advancement in Medicine

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Abstract

Stem cell research in modern medicine has required decades of research,

experimentation, and changes in the way we practice healthcare. Stem cells provide a unique

way to gather, utilize, and proceed with regenerative processes in patients who suffer from

otherwise incurable diseases. The broad field of stem cell research has been narrowed down to its

subcategory of hematopoietic stem cells (HSTs). These stem cells specifically provide solutions

to problems such as the adverse effects of chemotherapy in the treatment of many blood cancers

as well as immunocompromised diseases. The ultimate origins, mechanisms, and treatment using

these stem cells are complex and multifaceted, with decades of study behind the work. Major

problems have arisen from the study; however, solutions have been provided. One example is the

pool of candidates to be used in bone marrow transplants (the origin of HSTs), which is

relatively low. Within these transplants, specific mechanisms have been used to repress and

induce genes, both cancer-causing and cancer-eradicating. The effects of chemotherapy have

been significantly reduced using these stem cells, which will provide steps towards ensuring

future medicinal practices regarding blood cancer.

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The Modern Implication of Hematopoietic Stem Cell Research Toward Regenerative

Tissue and Its Advancement in Medicine

Introduction

Stem cell research involves a variety of experiments that aim at the treatment of various

tissues and organs and the regeneration of targeted conditions in the body. There are two major

types of stem cells that can be utilized and are classified as either embryonic stem cells or adult

stem cells (Lo& Parham, 2009). Stem cells, as a definition, are cells that are not in full form and

serve as a basis to form more cells specifically towards an organ or tissue, i.e., brain stem cells

can produce a multitude of brain cells (Arai & Suda, 2022). In modern medicine applications,

hematopoietic stem cells (a branch of adult stem cells) are currently the only stem cells used to

treat disease as a regenerative mechanism and can be found in adult bone marrow (Aggarwal et

al., 2021). One treatment hematopoietic stem cells have been utilized for is for patients who

exhibit blood disorders (blood cancer) and, as a result, require chemotherapy (Mahla, 2016).

When used, hematopoietic stem cells provide protection from harmful chemotherapeutic

radiation and, as a result, have resulted in patients with disorders such as lymphoblastic leukemia

living longer and healthier lives after chemotherapy treatments (Frampton, 2020). The

production of renewed mature cells needed for treatments requires simply a few hematopoietic

stem cells and thus is a great candidate for research for regenerative treatment (King & Perrin,

2020). As important as it is to understand the mechanism for hematopoietic stem cells and their

role in regeneration, it is equally important to make note of the aging process and its eventual

decline and death, a process otherwise known as hematopoiesis (CIRM, 2023). As hematopoiesis

draws near, issues can begin within the body, specifically malignancies within the blood system.

There has, however, been more research aiming toward the reverse aging of stem cells that can
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simultaneously reverse these malignant risks (Fuchs, 2020). While it has been established that

hematopoietic stem cells have proven to be ground-breaking in their role in chemotherapy effect

reversal, there are certain prerequisites required in the donor-patient relationship. As the source

of these cells arises from bone marrow, a donor is required to have the same matching blood type

and bone marrow as its intended recipient (Krishnan, 2022). It has also been proven that children

who receive these stem cells when no donor is available can use their younger siblings' blood as

a viable source. Stem cell research is ongoing and is an important example of the innovative

technologies that not only aim to improve the quality of treatment for patients but also provide

avenues for patients with no other viable treatment options.

Discussion:

Hematopoietic stem cell origin to advancement

The origin of hematopoietic stem cell research can be traced to the progression of

microscope technology. King and Perrin (2020) posit that through an experiment in the 1950s

with mice, Ernest McCulloch performed the first bone marrow transplantation, and the

conclusion gave rise to the idea that one transplantation gave a multiplex of lineage colonies. The

discovery and development of atomic weaponry in the early 20th century proved to be a change in

the understanding of the hematopoietic stem cell (Lo& Parham, 2009). Atomic weapons led

scientists to investigate how the ionizing radiations damage body tissues and medical ways

through which these adverse effects could be reversed. Further experimentation with bone

marrow transplantation saw a reversal of radiation effects, thus beginning the study of

regenerative hematopoietic stem cells. This discovery was most important after World War II,

when nuclear bombs were dropped in Hiroshima and Nagasaki in Japan (Aggarwal et al., 2021).

Survivors in these cities were exposed to lethal doses of ionizing radiation and experienced
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complete blood formation failure. The discovery of the microscope led to the discovery that bone

marrow was the most radiosensitive tissue in the body. This background offered a reason why

the victims were suffering from blood formation failure but failed to provide a solution to saving

their lives. Further investigation indicated that hematopoietic stem cells play a vital role in the

production of blood cells (Krishnan, 2022). Scientists discovered that by replacing the blood-

forming systems that were already destroyed by the radiation with new sources of lymphoid and

myeloid cells. This realization was the launching pad for many other medical discoveries that

could save lives in the future (Kubota & Kimur, 2019). Today, hematopoietic stem cells are

answers to many diseases that would be incurable, and with further development in technology

and further clinical inquiry into their functioning, more discoveries might be made in the future,

saving even more lives.

When discussing the origin of function, the aforementioned stem cells begin in the

embryonic stage and serve as a function to provide oxygen to the required stages of embryonic

development. It can be noted that throughout the embryonic process, hematopoietic stem cells

vary in function depending on the level of development from embryo to adulthood (Ballen et al.,

2016). Before progressing to bone marrow, where it spends most of its dormancy, hematopoietic

stem cells reside in the liver, where a renewing cycle of stem cells occurs frequently. When in

bone marrow, adults in their exhibition of the cells are located specifically close to the bone’s

surface, where maintenance of the stem cells can be restored regularly (CIRM, 2023).

Hematopoietic stem cells can also be found in the peripheral blood and the umbilical cord blood.

All blood cells come from the functional maturation of hematopoietic stem cells, which are rare

and multipotent.
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These cells

proliferate through self-renewal and differentiation (Aggarwal et al., 2021). Only a small

population of hematopoietic stem cells is needed to start off an entire

hematopoietic process.

Mechanism

The mechanism for transplantation can be divided into steps and is largely dependent on

the patient’s specific disease as well as the desired result of treatment. Mechanistic steps must

also take into consideration the availability of stem cells at hand (Weissman, 2024). The majority

of patients who undergo treatment utilizing hematopoietic stem cells suffer from acute myeloid

leukemia and can be treated with higher doses of chemotherapy (National Cancer Institute,

2015). Acute myeloid leukemia leads to the uncontrolled proliferation of the myeloid within the

bone marrow and the peripheral blood. Research data indicates that extended exposure to

ionizing radiation and some chemicals, such as herbicides, cigarette smoke, benzene, and

insecticides, can increase the risk of getting acute myeloid leukemia (Arai & Suda, 2022).

Radiation-induced leukemia involves the accumulation of irreparable genetic mutations within

the cells. This genetic damage hinders the cells’ ability to self-repair through the use of “base
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excision repair (BER), mismatch-mediated repair (MMR), homologous recombination (HR), and

non-homologous end joining” (Sumbly et al., 2022). Scientific estimations show that most cases

of radiation-induced acute myeloid leukemia occur three to 10 years after the initial exposure.

Therapy-related acute myeloid leukemia is thought to be a direct result of chemotherapy-induced

genetic mutations (Krishnan, 2022). When discussing the treatment of damage caused by

chemotherapy, stem cells are utilized using autologous hematopoietic stem cells, a subcategory

of the cell type (Frampton, 2020). Even though most effects of therapy-induced acute myeloid

leukemia are attributed to alkylating agents, some medications also used in cancer treatment,

such as fludarabine and azathioprine, have also been found to play a significant role (National

Cancer Institute, 2015). Therapy-induced leukemia is thus a combination of radiation and

chemical factors. Higher doses of chemotherapy and medication could result in life-threatening

complications. Doctors use hematopoietic stem cell transplantation (HSCT) to overcome the

challenge where higher doses of chemotherapy and medication are needed without posing a

significant risk to the patients’ health (Ballen et al., 2016). After a patient undergoes

chemotherapy, they are given an infusion of blood-forming stem cells to help in the restoration

of their bone marrow. The stem cell transplant in this case is known as an autologous SCT and

involves the collection of the patient’s stem cells before they undergo chemotherapy (Lee &

Hong, 2020). After the high doses of chemotherapy, the stem cells are then reinfused to enhance

the recovery of the already destroyed bone marrow. This mechanism allows for the direct

reversal of the toxic effects of radiation therapy.

In another function, hematopoietic stem cells can be used when bone marrow is damaged.

This kind of stem cell transplant is known as an allogeneic stem cell transplant. The donor in this

case is usually a close relative or any other matched donor (Messina et al., 2022). When
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received, the bone marrow is used to produce any enzymes that were deficient in the patient's

disease as well as aid in tumor-repressing gene production. This process is done through a

careful stage by reversing the effect of graft- vs. -tumor, otherwise known as the GvT effect

(National Cancer Institute, 2015). By eradicating this, the stem cells manage to reverse the

cancerous effects it causes.

Umbilical cord blood is another source that can be used to harvest hematopoietic stem

cells and can help patients with disorders and diseases that can be cured with allogeneic

hematopoietic cell transplantation (Ballen et al., 2018). In its initial phases, this kind of

transplantation was mainly limited to children due to the low dose of cells that were infused

(Orlic & Cannon, 2017). Through continued advancements that emphasize sufficient cell dosage

and human leukocyte antigen matching, Umbilical cord blood transplantation has been extended

to include adults with better outcomes and has shown higher success rates in treating various

hematologic disorders and metabolic diseases (Sumbly et al., 2022). Double-umbilical cord

blood transplantation and better supportive care have also been essential in increasing the

success rates of the procedure. The use of this medical technology extends access to

transplantation for patients who need it, especially those with diverse racial and ethnic

backgrounds (Wang et al., 2023). Only 30% of the patients who need hematopoietic stem cell

transplants have an HLA-matched relative donor, making umbilical cord blood a more reliable

and available source of stem cells for transplantation (Fuchs, 2020). Ballen et al. (2018) claim

that over 600,000 units of umbilical cord blood are stored globally with the aim of being used for

transplants, with over 30000 transplants already performed.

Hematopoietic stem cell gene therapy is another promising medical invention where

doctors take out hematopoietic stem cells and modify them before putting them back. This
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process involves the modification of the patient’s hematopoietic stem cells through the use of

viral factors (Nickel, 2019). The genetically modified hematopoietic stem cells can then be

transplanted back into the patient, providing a stable and lifelong source of self-renewing stem

cells and their blood cell progeny. The main aim of this procedure is to provide the patient with a

stable supply of genetically collected cells that may have potential benefits for various tissues

and organs in the body, including the central nervous system (Orlic & Cannon, 2017). The past

two decades have witnessed the success of hematopoietic stem cell gene therapy, especially in

treating severe combined immune deficiency (SCID), sickle cell anemia, and thalassemia.

The Future of Hematopoietic Stem Cell Research

The past has seen milestones covered in the application of hematopoietic stem cells in

combating various medical needs. Through these developments, the healthcare field has been

able to treat disorders that would otherwise be uncurable (Nickel, 2019). Additionally, medical

inventions have led to the improvement of umbilical cord blood as a more reliable source of

hematopoietic stem cells. In the future, researchers aim to improve umbilical cord blood

transplantation through various techniques such as homing techniques, nurturing procedures,

optimal unit selection, and immune recovery enhancement (Orlic & Cannon, 2017). These

improvements are meant to improve the already promising procedure and make it more effective

in the future.

Another major future invention that is expected to revolutionize the use of hematopoietic

stem cells is the reversion of mature cells into hematopoietic stem cells. This has never been in

the past, but a promising project by Havard Stem Cell Institute researchers has achieved to revert

mature cells from mice into blood-forming stem cells (HSCI, 2023). The reverted stem cells self-

renew and produce all forms of cellular components like regular hematopoietic stem cells.
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Although this project is still in its early stages, it has promising results and will solve some of the

major issues facing hematopoietic stem cell transplantation. The first issue will be reducing the

need for a compatible donor during transplantation. 70% of patients who undergo hematopoietic

stem cell transplantation do not have an identifiable match, and this will be a great relief for them

(King & Perrin, 2020). This will reduce the need for autologous stem cell transplantation, which

is sometimes slow and tedious due to a lack of a matching donor. The development may also

eliminate the need for hematopoietic stem cell harvesting in the bone marrow, which is much

more complicated than harvesting mature blood cells from many parts of the body. However,

even though the perceived benefits of this project are many, critics still fear the cost and

availability factors of the development (Messina et al., 2022). The process of reverting mature

cells requires high skills and equipment that are only available in special places like Harvard

University. When applied, a patient will need to have their mature cells harvested, reverted to

hematopoietic stem cell transplantation, and reinfused back into the body. This process requires

access to the combination of these skills and equipment within the patient’s reach (Nickel, 2019).

The unavailability of these two factors may lead to a high price for this procedure, further

reducing its accessibility for the majority of poor people in society. Additionally, the widespread

results of this procedure may not be experienced in the near future, as it may take years, if not

decades (Müller et al., 2016). However, given the benefits that the project is aimed at bringing to

the field of hematopoietic stem cell transplantation, it is still something to look up to.

Conclusion

Hematopoietic stem cells offer a transformative innovation to modern medicine and have

deepened our understanding of regenerative medicine. Treatment of diseases otherwise treated

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by chemotherapy has significantly saved the lives of patients suffering from its adverse effects.

Through the mechanisms discussed, this advancement has been thoroughly researched,

experimented with, and resulted in both cost-efficient and healthcare-efficient applications for

treating a diverse range of blood diseases, as well as providing an alternative step for the ultimate

cure of cancer. Bone marrow transplantation, from its origin to modernity, has allowed for

regenerative treatment that has allowed for hematopoietic stem cells to be utilized in a way that

has never been utilized before. A pivotal facet of employing these cells necessitates

consideration of their application and the origin of their roots. Gathering these cells in

themselves is a tactful process. Only those who suffer from these diseases should ethically use

the processes described above, as there is a limited pool of donors that provide such necessities.

There have been innovative tools used, however, that have provided children with the

opportunity to utilize matches from their identical twins to use bone marrow in an otherwise dry

pool.

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