**3.1 Tissue-resident adult stem cells**

Tissues and organs in our body constantly regenerate throughout our lives. Human red blood cells have a defined life span of 120 days [54]. The lining in the intestine turns over completely about every 7 days [55]. Skin cells are constantly shed and then renewed. Endothelial cells in the human heart have a > 15% turnover rate per year, while cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood [56]. These are examples of cell turnover at a steady state. Some organs, such as the liver, display relatively slow tissue turnover at a steady state, however upon damage, undergo bursts of cell proliferation and repair [57]. Essential for such replenishment and repair in postnatal life are the activities of adult stem cells. Adult stem cells are undifferentiated tissue-resident cells capable of self-renewal and differentiation within the tissue or organ. Self-renewal allows replication of themselves to sustain their population, and differentiation enables replenishment of various mature cell types upon tissue remodeling and repair, to maintain tissue homeostasis throughout postnatal life.

Hematopoietic stem cells (HSCs) are the first identified adult stem cells [58, 59]. The idea of HSCs, however, can be traced back before the experimental proof of HSCs and following the atomic bombing of Hiroshima and Nagasaki, when the civilians exposed to irradiation were documented to have symptoms of hematopoietic failure. Subsequent experiments in mice demonstrated recovery of the hematopoietic system after radiation injury by bone marrow transplantation [60]. These studies and subsequent transplantation experiments in mice with acute leukemia [61] led to pioneering of allogeneic hematopoietic stem cell transplantation (alloHSCT) by Thomas et al. in patients treated with radiation and chemotherapy in 1957 [62]. At that time, little was known about HLAs, and there was no matching between donors and recipients, until the mid-late 1960, when methods to identify HLA were developed [63]. While many physicians had doubts on the approach of alloHSCT, Thomas et al. persevered and performed transplantation using a matched sibling donor for a patient with leukemia in 1969 [64, 65]. Eight years later, his team performed the first HLA-matched transplant from an unrelated donor, a success that led to the formation of a national registry of bone marrow donors [63]. Dr. Thomas received the 1990 Nobel Prize in Physiology or Medicine with Dr. Joseph Murray, who performed the first successful kidney transplant, for their contribution to cell and organ transplantation.

For decades, hematopoiesis has been described as a cellular hierarchy where only one type of HSC is sitting at the apex of the hierarchy and giving rise to lineagerestricted progenitors, which further differentiate into all the cell types of the blood [66]. However, accumulating data on single HSC repopulation and serial transplantation have revealed an inherent heterogeneity in self-renewal and multi-lineage differentiation of HSCs [67, 68]. These and other studies have contributed to a change of view on HSCs from a single stem cell-type hierarchy model to a consortium model where a pool of stem cells with slightly different properties regenerate all the blood types [69–71]. However, a recent study suggested that platelet-biased stem cells, primed toward the megakaryocyte lineage, reside at the apex of the HSC hierarchy [72]. To reconcile with different observations on HSCs, a new speculative

**107**

a stemlike state [73].

**Figure 3.**

*stem cells.*

response to environmental stimulation [73].

**3.2 Adult stem cell niche and aging**

*Innovations in Human Stem Cell Research: A Holy Grail for Regenerative Medicine*

model was further raised suggesting that stem cells are rare reserve cells that occasionally generate lineage-restricted progenitors [73]. Some progenitors may retain a degree of developmental flexibility and, during extreme stress, can revert to

*Identification of adult stem cells from postnatal organs and tissues such as the brain, eye, teeth, lung, heart, kidney, intestine, skeletal muscle, fat tissue, bone marrow, skin, and reproductive system. Human placenta and cord blood are also rich in different hematopoietic stem cells and progenitors, as well as non-hematopoietic* 

Adult stem cells have been identified in most, if not all, tissues and organs in our body, as well as the placenta and cord blood (CB) (**Figure 3**). Extensive studies have been performed to characterize the adult stem cells in the fast-regenerating organs such as the skin and intestine [74, 75]. Moreover, the organs that were once thought to be non-regenerative, such as the brain and heart, also contain adult stem cells, i.e., neural stem cells and cardiac stem cells, respectively [76, 77]. In addition, similar to the evolving concept of hematopoiesis [73], heterogeneity of stem cell populations in distinct compartments in these organs has also been demonstrated, and the heterogeneity enables them to adapt to diverse roles and functions in

It has been well accepted that the activities of adult stem cells, whether they stay quiescent or undergo activation, are largely instructed by the microenvironment they reside in, i.e., stem cell niche. Extensive studies have been performed to characterize the stem cell niche in different organ systems such as the skeletal muscle, bone marrow, skin, intestines, and brain (reviewed in [78]). There are common features of the adult stem cell niche. In general, the stem cell niche or microenvironment is composed of stem cells themselves and progeny, surrounding MSCs or stromal cells, extracellular matrix, and adhesion molecules, as well as the external cues from distant sources (long-range signaling factors) [78]. Collectively, both cellular and acellular components of the stem cell niche create a complex microenvironment maintaining stem cell fate and ensuring robust regenerative responses to external stimuli. Although other signaling pathways have been described, TGFβ

*DOI: http://dx.doi.org/10.5772/intechopen.88790*

*Innovations in Human Stem Cell Research: A Holy Grail for Regenerative Medicine DOI: http://dx.doi.org/10.5772/intechopen.88790*

### **Figure 3.**

*Innovations in Cell Research and Therapy*

**3. Adult (somatic) stem cells**

**3.1 Tissue-resident adult stem cells**

data for the treatment of steroid-resistant aGvHD in a phase 1 trial. Cynata plans to advance the cell product into phase 2 trials for GvHD and critical limb ischemia.

Tissues and organs in our body constantly regenerate throughout our lives. Human red blood cells have a defined life span of 120 days [54]. The lining in the intestine turns over completely about every 7 days [55]. Skin cells are constantly shed and then renewed. Endothelial cells in the human heart have a > 15% turnover rate per year, while cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood [56]. These are examples of cell turnover at a steady state. Some organs, such as the liver, display relatively slow tissue turnover at a steady state, however upon damage, undergo bursts of cell proliferation and repair [57]. Essential for such replenishment and repair in postnatal life are the activities of adult stem cells. Adult stem cells are undifferentiated tissue-resident cells capable of self-renewal and differentiation within the tissue or organ. Self-renewal allows replication of themselves to sustain their population, and differentiation enables replenishment of various mature cell types upon tissue remodeling and repair, to maintain tissue homeostasis throughout postnatal life. Hematopoietic stem cells (HSCs) are the first identified adult stem cells [58, 59]. The idea of HSCs, however, can be traced back before the experimental proof of HSCs and following the atomic bombing of Hiroshima and Nagasaki, when the civilians exposed to irradiation were documented to have symptoms of hematopoietic failure. Subsequent experiments in mice demonstrated recovery of the hematopoietic system after radiation injury by bone marrow transplantation [60]. These studies and subsequent transplantation experiments in mice with acute leukemia [61] led to pioneering of allogeneic hematopoietic stem cell transplantation (alloHSCT) by Thomas et al. in patients treated with radiation and chemotherapy in 1957 [62]. At that time, little was known about HLAs, and there was no matching between donors and recipients, until the mid-late 1960, when methods to identify HLA were developed [63]. While many physicians had doubts on the approach of alloHSCT, Thomas et al. persevered and performed transplantation using a matched sibling donor for a patient with leukemia in 1969 [64, 65]. Eight years later, his team performed the first HLA-matched transplant from an unrelated donor, a success that led to the formation of a national registry of bone marrow donors [63]. Dr. Thomas received the 1990 Nobel Prize in Physiology or Medicine with Dr. Joseph Murray, who performed the first successful kidney transplant, for their contribution to cell and organ

For decades, hematopoiesis has been described as a cellular hierarchy where only

one type of HSC is sitting at the apex of the hierarchy and giving rise to lineagerestricted progenitors, which further differentiate into all the cell types of the blood [66]. However, accumulating data on single HSC repopulation and serial transplantation have revealed an inherent heterogeneity in self-renewal and multi-lineage differentiation of HSCs [67, 68]. These and other studies have contributed to a change of view on HSCs from a single stem cell-type hierarchy model to a consortium model where a pool of stem cells with slightly different properties regenerate all the blood types [69–71]. However, a recent study suggested that platelet-biased stem cells, primed toward the megakaryocyte lineage, reside at the apex of the HSC hierarchy [72]. To reconcile with different observations on HSCs, a new speculative

**106**

transplantation.

*Identification of adult stem cells from postnatal organs and tissues such as the brain, eye, teeth, lung, heart, kidney, intestine, skeletal muscle, fat tissue, bone marrow, skin, and reproductive system. Human placenta and cord blood are also rich in different hematopoietic stem cells and progenitors, as well as non-hematopoietic stem cells.*

model was further raised suggesting that stem cells are rare reserve cells that occasionally generate lineage-restricted progenitors [73]. Some progenitors may retain a degree of developmental flexibility and, during extreme stress, can revert to a stemlike state [73].

Adult stem cells have been identified in most, if not all, tissues and organs in our body, as well as the placenta and cord blood (CB) (**Figure 3**). Extensive studies have been performed to characterize the adult stem cells in the fast-regenerating organs such as the skin and intestine [74, 75]. Moreover, the organs that were once thought to be non-regenerative, such as the brain and heart, also contain adult stem cells, i.e., neural stem cells and cardiac stem cells, respectively [76, 77]. In addition, similar to the evolving concept of hematopoiesis [73], heterogeneity of stem cell populations in distinct compartments in these organs has also been demonstrated, and the heterogeneity enables them to adapt to diverse roles and functions in response to environmental stimulation [73].
