**3. Origin & deposition of hematopoietic and non-hematopoietic stem cells in bone marrow**

Early embryogenesis is the most active period for the developmental migration/trafficking of stem cells. With the beginning of gastrulation and organogenesis, stem cells migrate to places where they establish rudiments for new tissues and organs. At certain points, of development stem cells colonize tissue specific niches, where they reside as a population of self renewing cells supplying new cells that effectively replace senescent ones or those undergoing apoptosis.

In mammals the first primitive HSC are found in the yolk sac and first definitive HSC a few days later in the aorta-gonadmesonephros (AGM) region [35]. From the yolk sac and/or AGM region HSC migrate to the fetal liver (FL), which during the second trimester of gestation becomes the major mammalian hematopoietic organ. By the end of the second trimester of gestation, HSC leave the fetal liver and colonize BM tissue. Signals for the translocation of HSC from the fetal liver to BM are provided by the alpha chemokine – SDF-1 that is secreted by osteoblasts lining the developing marrow cavities, marrow fibroblasts and endothelial cells. In response to SDF-1, HSC that expresses, SDF-1 receptor-a seven transmembrane-spanning G protein coupled CXCR4 receptor, leave the fetal liver and begin to home into BM where they finally establish adult haematopoiesis.

74 Blood Cell – An Overview of Studies in Hematology

Freshly isolated TCSC from the BM express tissue committed markers

TCSCs express c-Kit which is a more differentiated marker not expressed by PSCs.

as opposed to the existing notion that HSC sit at the apex of hematopoietic system [1].

Thus we propose following developmental hierarchy of stem cells in bone marrow (Figure:2)

The existing controversial literature that HSCs and MSCs can trans-differentiate into various lineages can be alternatively explained by the presence of these pluripotent stem cells. These PSCs interact closely with the MSCs by a process defined as emperipolesis [34]. The MSCs secrete SDF-1(Stromal Derived Factor-1) and other chemo-attractants thereby creating a homing environment for these pluripotent stem cells (express CXCR4). Thus isolated BM stem cells have always been contaminated with these PSCs which may have resulted in trans-differentiation and that HSCs/MSCs (being lineage restricted themselves) possibly do

**3. Origin & deposition of hematopoietic and non-hematopoietic stem** 

Early embryogenesis is the most active period for the developmental migration/trafficking of stem cells. With the beginning of gastrulation and organogenesis, stem cells migrate to places where they establish rudiments for new tissues and organs. At certain points, of development stem cells colonize tissue specific niches, where they reside as a population of self renewing cells supplying new cells that effectively replace senescent ones or those

PSCs in BM acquire these markers after many days in culture

**Figure 2.** Developmental hierarchy of stem cells in bone marrow

not account for the observed plasticity.

**cells in bone marrow** 

undergoing apoptosis.

It is very likely that at this point BM is also colonized by several other nonhematopoietic stem cells that may circulate during organogenesis and rapid foetal growth/expansion. In support of this stem cells for different tissues express CXCR4 on their surface and follow an SDF-1 gradient. Thus the SDF-1-CXCR4 axis alone or in combination with other chemoattractants plays a crucial role in the accumulation of non-hematopoietic stem cells in developing BM [36, 37]. These cells find a permissive environment to survive in BM, and may play an underappreciated role as a reserve pool of stem cells for organ/tissue regeneration during postnatal life.

The presence of these various populations of stem cells in the BM (Table 1) is a result of the 'developmental migration' of stem cells during ontogenesis and the presence of the permissive environment that attracts them to the BM tissue. HSC and other nonhematopoietic stem cells are actively chemoattracted by factors secreted by BM stromal cells and osteoblasts (e.g. SDF-1), hepatocyte growth factor (HGF)) and colonize marrow by the end of the second and the beginning of the third trimester of gestation [24].

It is assumed that these non-hematopoietic pluripotent stem cells are deposited in the BM during early embryogenesis and subsequently may be mobilized in stressed situations and circulate in the peripheral blood. Similarly due to the stress of delivery these cells may also be present in cord blood [18].

Interestingly various terminologies like MAPCs, MIAMI, RS cells etc. (Table 1) disappeared from the literature after initial publications and excitement except VSELs. Ratajczak and group have made tremendous contribution to the field of VSELs biology. At present various laboratories across the world are providing evidence to support the pluripotent property and potential of VSELs isolated from cord blood and bone marrow [38]. Possible reason being the method to isolate VSELs by flow cytometry described by Ratajczak and group could easily be replicated in various labs across the world.
