**1. Introduction**

68 Blood Cell – An Overview of Studies in Hematology

Journal of Neurosurgery February, Vol. 62 (2):200-205

[131] Edward H. Stullken, Jr., William E. Johnston, Jr.,Donald S. Prough, Francis J. Balestrieri, and Joe M. McWhorter, (1985), Implications of nimodipine prophylaxis of cerebral vasospasm on anesthetic management during intracranial aneurysm clipping,

> In a short span of few years, the possibility that the human body contains cells that can repair and regenerate damaged and diseased tissue has become a reality. Adult stem cells have been isolated from numerous adult tissues, umbilical cord, and other non-embryonic sources, and have demonstrated a surprising ability for transformation into other tissue and cell types and for the repair of damaged tissues.

(Image: Hematopoiesis\_ (human) \_diagram.png by A. Rad)

**Figure 1.** Hematopoiesis in Bone Marrow

© 2012 Shaikh and Bhartiya, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 Shaikh and Bhartiya, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In the 1950s, researchers discovered that the bone marrow contains stem cells i.e. hematopoietic stem cells (HSC) with the ability to self-renew and give rise to cell types in the blood and immune system (Figure1). Multipotent HSCs reside at the apex of hematopoietic hierarchy and they are connected to mature cells by a complex roadmap of progenitor intermediates. The HSC differentiate into two different kinds of progenitors viz. Common Myeloid Progenitors (CMP) and Common Lymphoid Progenitors (CLP), which further differentiate to various blood cells including platelets, granulocytes, lymphocytes and macrophages. As a result, bone marrow transplantation became the standard method of care for most hematopoietic malignancies whereby the HSCs were able to repopulate bone marrow after any kind of hematopoietic failure. A recent review by Doulatov et al [1] describes the knowledge gathered over the years on Hematopoiesis.

VSELs in Bone Marrow and Cord Blood 71

liver damage [11] and of MSC in skeletal regeneration [12], cardiac regeneration [13], diabetes [14] and osteogeneis imperfect [15]. The potential of adult stem cells also resulted in slow growth of research and funding restrictions on ES cells during President Bush regime in USA – based on the argument that destroying embryos to derive human ES cell lines was not essential, when better alternatives including adult stem cells are available for regenerative medicine (http://en.wikipedia.org/wiki/Stem\_cell\_controversy). However the excitement over plasticity of HSC reduced when their role in repair of damaged organs

Several alternative mechanisms were proposed to explain the trans-differentiation of bone marrow stem cells [18] including (i) epigenetic changes i.e. factors present in the environment of damaged organs may induce epigenetic changes in the genes that regulate pluripotency of HSCs (ii) cell fusion during which infused HSCs may fuse with cells in damaged tissues and form heterokaryons which express markers of both donor and recipient cells (iii) paracrine effect i.e. HSCs are source of different trophic and angiopoietic factors that may promote tissue/organ repair (iv) microvesicles- dependent transfer of molecules like receptors, proteins and mRNA between HSC and damaged cells and (iv) **presence of pluripotent stem cell population in the bone marrow in addition to HSC & MSC that may contribute to regeneration**. Presence of other stem cells in the BM may also explain the loss of contribution of BM cells to organ regeneration with the use of highly purified population of HSC [16]. Of these various possibilities (i) and (ii) are extremely rare and most likely the fact that BM houses heterogeneous and perhaps pluripotent stem cells may explain transdifferentiation potential of bone marrow. It has been demonstrated that there are heterogeneous stem cell populations in adult bone marrow compartment. Under appropriate experimental conditions, a certain type of bone marrow stem cells appears to differentiate (or transdifferentiate) into a variety of non-haemopoietic cells of ectodermal, mesodermal and endodermal origins (such as myocytes, neural cells and hepatocytes) [67].Various investigators have reported pluripotent stem cells in the bone marrow by using

varied approaches to demonstrate their presence and are listed in Table 1.

The potential relationship of the BM-derived pluripotent stem cells reported by various investigators and compiled in Table1 is not clear. It is possible that these are overlapping populations of cells identified by slightly different isolation/ expansion strategies and likely that all of these versatile BM-derived Oct-4+ non-hematopoietic stem cells, which were given different names, are in fact very closely related to the same type of BM-residing Pluripotent Stem Cells (PSC). This overlap was elegantly described earlier by Ratajczak and his group [25] that various investigators are looking from different "keyholes" at the same population of stem cells that are hiding in a "darkroom" of the bone marrow environment. They further suggested that a 'founder cell' may exist in the bone marrow which is responsible for multi-lineage differentiation. Table 2 is a compilation of various markers reported on these differently described PSCs in the bone marrow responsible for their mobility (CXCR4), pluripotency (Oct-4, Nanog, Rex, Tert), non-hematopoietic lineage (CD45), immune status (MHC-1) and their developmental migration similarity to PGCs

became controversial [16, 17].

(SSEA1).

Besides HSC, another stem cell population, the mesenchymal stem cells (MSC) was identified in the bone marrow about 40 years ago [2]. MSCs comprise of the adherent stem cell population with immune-modulatory properties. Besides bone marrow, MSCs can also be extracted from virtually all post-natal as well as extra-embryonic tissues such as amniotic membrane, placenta and umbilical cord. They can differentiate along multiple lineages and exhibit significant expansion capability *in vitro*. Co-transplantation with MSCs improves engraftment of HSCs after autologous intra-bone marrow transplantation [3]. MSCs are also considered useful as vehicles for emerging cell and gene therapies in the field of tissue engineering [4]. Recently it has been postulated that MSC provide the conducive microenvironment for HSCs and thus maintain the stemness and proliferation of HSCs and support HSC transplantation [3].
