Article

ISSN 0006-2979, Biochemistry (Moscow), 2024, Vol. 89, No. 2, pp. 269-278 © Pleiades Publishing, Ltd., 2024.

269

REVIEW

Organ Frame Elements or Free Intercellular

Gel-Like Matrix as Necessary Conditions

for Building Organ Structures during Regeneration

Vasily N. Manskikh

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University,

119991 Moscow, Russia

e-mail: manskikh@mail.ru

Received September 14, 2023

Revised November 2, 2023

Accepted November 15, 2023

Abstract— Over the past decades, an unimaginably large number of attempts have been made to restore the struc-

ture of mammalian organs after injury by introducing stem cells into them. However, this procedure does not lead

to full recovery. At the same time, it is known that complete regeneration (restitution without fibrosis) is possible

in organs with proliferating parenchymal cells. An analysis of such models allows to conclude that the most im-

portant condition for the repair of histological structures of an organ (in the presence of stem cells) is preserva-

tion of the collagen frame structures in it, which serve as “guide rails” for proliferating and differentiating cells.

An alternative condition for complete reconstruction of organ structures is the presence of a free “morphogenetic

space” containing a gel-like matrix of the embryonic-type connective tissue, which exists during embryonal devel-

opment of organs in mammals or during complete regeneration in amphibians. Approaches aimed at preserving

frame structures or creating a “morphogenetic space” could radically improve the results of organ regeneration

using both local and exogenous stem cells.

DOI: 10.1134/S000629792402007X

Keywords: regenerative medicine, regeneration, embryonic connective tissue, morphogenetic framework, stem cells

INTRODUCTION

The notion that regeneration of organs after in-

jury is one of the most important and still unresolved

problems in biology and medicine hardly needs justifi-

cation. Some aspects of this problem, such as roles of

various cytokines, stromal and stem cells, have been

investigated in great detail, while others have not

practically been discussed in the literature. This work

is devoted to consideration and justification of the ap-

proach to full regeneration (restitution) of organ struc-

tures, which has never been considered as a general

key requirement, although several examples of suc-

cessful realization of this approach in experimental

models have been reported. It seems that non-compli-

ance with this requirement is the reason for regular

failures of the attempts to regenerate organs both in

experiments and in clinic through introduction of var-

ious growth factors and stem cells.

UNSUCCESSFUL ATTEMPTS

TO REGENERATE ORGAN STRUCTURES

AFTER INJURY WITH THE HELP OF STEM CELLS

First attempts to achieve complete regeneration

of organs in mammals and humans by introduction of

stem cells (initially embryonic stem cells) after organ

injury have been made very long ago [1-16]. However,

the results of these attempts were discouragingly in-

significant. Although it was assumed at the beginning

that the cause of failures was incompatibility of donor

embryonic stem cells with the host organism, use of

induced autologous pluripotent cells did not improve

the situation [8]. At the same time, there is no doubts

that in many cases formation of new differentiated

cells (even formation of areas of the uniformly struc-

tured tissues such as, for example, myocardium) from

the transplanted pool of stem cell has been observed

[1-16]. However, the complex organ structures (such

MANSKIKH270

BIOCHEMISTRY (Moscow) Vol. 89 No. 2 2024

as nephrons) as well as whole organs was not possi-

ble to regenerate. Obviously, in this case the suggested

initial concept implying that the pool of stem cells is

the main component required for organ regeneration

contradicts the available experimental data. Contradic-

tions of this concept to two other groups of the facts

also exist: (i) pool of stem cells is always present in

many organs such as skin, gastrointestinal tract, liver,

kidneys; (ii)proliferation of the relatively differentiat-

ed elements plays the main role in reparative regen-

eration under natural conditions because stem cells in

normal tissues are present in very small numbers (less

than 0.1% of population) and they divide quire rarely,

but regeneration occurs within a relatively short time.

Hence, stem cells are more important for self-mainte-

nance of cell population, than for reparative regenera-

tion itself [17].

Unsuccessful attempts of using stem cells resulted

in the shift of research direction towards investigation

of the role of ‘stem-cell niches’ and cytokines in regen-

eration [16, 18-22]. But not much attention has been

paid to the group of facts indicating that the organs

with their own pool of proliferating parenchyma cells

are capable in a number of cases completely regener-

ate their structure after damage.

STEM AND OTHER PROLIFERATING CELLS

ARE PRESENT IN MANY ORGANS AND

ARE CAPABLE OF REGENERATING

THE ORGAN STRUCTURE

UNDER CERTAIN CONDITIONS

Such parenchymatous organs in mammals as liv-

er and kidney are capable of complete regeneration of

their structure in the case of certain types of damages.

In particular, complete regeneration of liver structure

is possible under the action of thioacetamide causing

apoptosis (but not necrosis) with active proliferation

and hypertrophy of the remaining hepatocytes [23, 24]

(Fig. 1, a and b). It is well-known from clinical obser-

vations that outcome of the acute (contrary to chronic)

kidney failure in the vast majority of cases (upon re-

covery) consists of complete restoration of the nephron

structure without the development of chronic kidney

failure [25-27]. Obviously, this is associated with the

fact that these organs have their own pool of low-dif-

ferentiated cells (including stem cells) without which

regeneration is impossible, similar to impossibility

of regeneration after myocardium infarction [3, 14].

However, presence of the pool of stem cells in these or-

gans does not necessary leads to regeneration of the

damaged organ. Moreover, failure of regeneration is

observed in most cases of damages especially under

chronic infectious hepatitis and toxic liver damage,

which results in liver cirrhosis or under pyelonephri-

tis and infarctions leading to development of rough

scars in kidneys [25]. Comparison of the conditions

leading to these two outcomes could be very useful for

understanding the mechanisms of complete regener-

ation. In this respect the case of acute toxic damages

of kidneys that results in mass death of epithelial cells

in renal tubules and their removal with urine without

destruction of basement membranes is very interest-

ing. As has been mentioned above, acute kidney fail-

ure developing during intoxication, as a rule, ends

with complete restoration of the nephron structure.

However, in the rare occasions, when the acute kid-

ney failure leads to the development of chronic kidney

failure with fibrosis (such as in the cases of mercury

compaunds poisoning), it is necessarily accompanied

by not only death of epithelia in renal tubules, but

also by tubulorrhexis with basement membrane dam-

age, appearance of urine components and residues of

necrotised cells in interstitium, and development of

inflammation [25]. Similarly, if not the small doses of

thioacetamide are used to induce experimental liver

damage, but other damage-inducing agents causing

necrosis (but not apoptosis) of hepatocytes with devel-

opment of inflammation, liver fibrosis is observed in

these experiments [23, 24, 28] (Fig.1, candd).

Another remarkable example is regeneration of

testicle. Following exposure to moderate radiation

spermatogenic cells are almost completely killed, but

basic three-dimensional structure of the testis tubules

is maintained, therefore, organ structure is completely

restored after certain time; in the case of mechanical

damage or chemical necrosis the affected part is sub-

jected to resorption with time, and its space is filled via

elongation of the preserved testis tubules growing in

the direction away from testicular network [29].

These examples imply that not only the organs

with own pool of stem cells are capable of complete

regeneration (restitution), but also provide indications

of the particular conditions that make this regenera-

tion either possible or impossible.

STEM CELLS ARE NOT CAPABLE

OF RECREATING ORGAN STRUCTURES

IN AN ADULT ORGANISM

It is important to note that although the elements of

stem system (primarily induced pluripotent stem cells)

have very wide potential for differentiation, this does

not mean that the possibility for building of complex

and ordered organ structures from these cells are equal-

ly as wide in a post-fetal organism. Architectural poten-

tial of stem cells is clearly visible in the case of tumor

growth especially of highly differentiated neoplasia.

In this case mass of tissue structures could be formed

such as plates, globules, alveoli, tubules, rosettes, and in

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BIOCHEMISTRY (Moscow) Vol. 89 No. 2 2024

Fig. 1. Development of complete (restitution) or incomplete (substitution) lever regeneration depending on the type of injury.

aandb)Regeneration of the C57BL/6 mouse liver after administration of thioacetamide: a)after 48h (mass apoptosis without

inflammation; verified using TUNEL-method (black nuclei in inset)); b) after 12days (complete regeneration of lobules with

signs of hepatocyte hypertrophy). candd)Regeneration of the C57BL/6 mouse liver after cryodamage: c)after 48h (necrosis and

inflammation, TUNEL-negative nuclei– see inset); d)after 12days (site of inflammation and fibrosis). In all images damaged

regions are shown with black stars. Scale bars and magnification: a-d)200µm, magnification– 100×, (inset in panela,20µm,

inpanelc,15µm; magnification– 1000×); staining with hematoxylin and eosin (insets in panels aandc,TUNEL-method). Images

made by the author[24].

special cases, such as nephroblastoma, primitive renal

glomeruli[30]. However, at this point the processes of

morphogenesis ends, and renal lobules or nephrons

are never formed from these cells. Even in the benign

teratomas the cited primitive elements are formed,

but not the complete organ fragments [31]. Cell-pre-

cursors behave similarly also in the cases, when the

organ “needs” to enhance its functional capabilities.

Inparticular, in the case of vicarious (replacing) kidney

hypertrophy there is no formation of new nephrons,

but rather increase of length of the existing tubules oc-

curs [24], which can be seen in histological images as

dramatic increase of the surface area occupied by the

tubules with sparsely distributed glomeruli (Fig. 2a).

In the case of kidney regeneration after acute necrot-

ic nephrosis, the non-damaged basement membranes

of tubules served as peculiar “guide rails” along which

the proliferating cells could rebuild the destructed el-

ements of nephrons form glomeruli to collecting tu-

bules; that is why tubulorrhexis makes nephron re-

generation impossible [25]. Exactly the same situation

takes place in the liver lobules, which only increase

in size in the case of liver hypertrophy, but are nor

formed de novo, and in testis, where after damage the

existing tubules elongate, but new ones are not formed.

Hence, stem cells present in the regenerating tis-

sues or introduced exogenous stem cells are capable

of incorporation into already existing structures (as

during physiological regeneration), but they are not ca-

pable of building new structures due to the absence of

required embryonic morphogenic gradients. Further-

more, the processes preventing regeneration along the

organ frame very often occur in the damaged tissues.

ORGAN FRAME ELEMENTS

AND THEIR ROLE IN CONSTRUCTION

OF ORGAN STRUCTURES

From the abovementioned examples, as well as

from many others, it seems obvious that the most im-

portant cause explaining impossibility of restitution is

disruption of architectonic of organ frame structures.

Frame elements include such formations of extracel-

MANSKIKH272

BIOCHEMISTRY (Moscow) Vol. 89 No. 2 2024

Fig. 2. Tissue responses upon hypertrophy and formation of new organ structures. a)BALB/c mouse kidney in the case of vi-

carious hypertrophy after ischemia of the second kidney (relative decrease of the number of glomeruli (shown with arrows)

on the background of the large surface area occupied by only tubules in the slice, marked with stars); b)kidney of a newborn

Chinchilla rabbit, subcapsular area of the cortex (metanephrogenic blastema and forming new nephrons are marked with stars);

c)“embryonic” connective tissue in the kidney medulla of the newborn Chinchilla rabbit (sparse amount of collagen and loose

reticular stroma; main unstructured substance of the connective tissue (marked with stars) fills the space between the forming

tubules); d) spontaneous adenocarcinoma of the Chinchilla rabbit uterus (metachromatically stained myxoid stroma resem-

bling embryonic connective tissue marked with stars). Scale bars and magnification: a)200µm, magnification– 100×; b)50µm,

magnification– 400×; c)20µm, magnification– 1000×; d)100µm, magnification– 200×. Staining techniques: aandb– hematox-

ylin and eosin staining; c– impregnation according to Gordon–Sweets followed by staining with Twort mixture (neutral red–

light green); d– thionine staining.

lular matrix that not only ensure mechanical stability,

but also have ordered structure corresponding to ar-

chitectonic of the organ, and it is exactly this architec-

tonic is provided by these components. At least three

types of such structures could be mentioned.

1)  Complex three-dimensional structure compris-

ing totality of basement membranes (mostly based on

type IV collagen in epithelia, and types III and V in

muscles, as well on perlecan, laminin, and numerous

components [31-34]), which together form a contour

basis of an elemental unit of a certain organ (hepatic

lobule, nephron, etc.); such frame structures are es-

sential for the organs with parenchyma made of epi-

thelial tissues and for muscle-based formations; role

of these structures is not only to provide stability, but

also to ensure ordered arrangements (for epithelia) or

support for combining elements into one mechanical

structure (for muscles).

2)  Three-dimensional network formed by reticu-

lin fibers (based on typeIII collagen), which comprise

frame structures in hematopoietic organs and organs of

immunogenesis (thymus, spleen, lymph glands, bone

marrow) or filling the space between the organ struc-

tures separated by basement membranes (in kidneys,

liver, etc.); reticulin formation allow compartmental-

ization of an organ (for example, they comprise the

basis of spleen follicles and lymph nodes) and at the

same time, they do not prevent locomotion of mobile

cells and even support them [31,32].

3)Special types of frame structures such as myelin

sheaths of axons in nerve cells, elastic membranes,

and various collagen fibers in vessel walls, main sub-

stance in eye cornea consisting of the type I collagen

fibers, and others.

It is very important to mention that the frame

structures arise during embryogenesis as a one system

for the whole organism simultaneously with formation

of all its compartments, which provides correspond-

ing morphogenic positioning effect on all differentiat-

ing cells. Such positioning information is maintained

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BIOCHEMISTRY (Moscow) Vol. 89 No. 2 2024

in an adult organism likely with the help of described

frame elements; that is why destruction of these ele-

ments prevents rebuilding of organ structures.

It must be noted that the frame structures of extra-

cellular matrix undoubtedly could affect intracellular

signaling pathways and most important cellular reac-

tions (prevent anoikis, induce specific cell differenti-

ation, etc.) [34, 35]. In particular, it is known that the

composition of laminins in the basement membrane

determines direction of differentiation of epithelial

cells (for example, laminin composition determines

what epithelia would develop in a particular section

of intestine) [36], development of reticulin fibers and

elastic framework predetermines compartmentaliza-

tion of lungs in embryogenesis [37], and reticulin fibers

and even type I collagen fiber bundles predetermine

branching of the developed ducts in mammary and

salivary glands [38-40]. It seems, however, that these

and similar effects are only an important addition to

the role of “guiding rails” during reconstruction of or-

gans in regeneration.

FACTORS PREVENTING RESTORATION

OF NORMAL ORGAN STRUCTURE

IN THE PRESENCE OF PROLIFERATING

PARENCHYMAL CELL-PRECURSORS IN THEM

If we accept the hypothesis that maintenance of

frame structures is the main condition for complete re-

generation of a damaged organ in adult mammals, we

can identify the factors preventing such regeneration.

Typical in fibrosis transformation of fibroblasts into

myofibroblasts actively secreting collagen and associ-

ated with this formation of scar tissues in mammals

should be mentioned in the first place [33,34]. On the

one hand, it appears that such tissues fill the space of

the organ making development of parenchymatous el-

ements impossible (due to mechanical and metabolic

reasons such as avascularity), and, on the other hand,

frame components of the organ are damaged in the

process. Fibroblasts and myofibroblasts are signifi-

cantly less demanding on conditions for survival and

proliferation in comparison with parenchymatous ele-

ments, and they fill the space of defect in tissues with

collagen much faster than the latter ones [25,41]. They

secrete matrix metalloproteases, which destroy colla-

gen of the organ frame structures and basement mem-

branes [33,34], and produce a large amount of fibrotic

collagen, which eventually leads to disruption of archi-

tectonics of the organ frame. It should be mentioned

that the key role of preserved guiding frame elements

has been recognized for the case of regeneration of

conductive structures in nervous system (nerves, spi-

nal cord) [42-44] and as inducer of bone tissue differ-

entiation [45-47], but, obviously, it has not been fully

considered in the cases of regeneration of parenchy-

matous organs (liver, kidney, myocardium, various

glands). On the other hand, this particular princi-

ple is used nowadays for creation of artificial organs

invitro, when for their construction decellularized col-

lagen scaffolds are used, which are seeded with stem

cells[48-52].

Another negative condition revealed through the

further analysis of available information is inflamma-

tion, which often leads to fibrosis even without mor-

phological signs of damage in the tissues [25]. This is

facilitated by the so-called M2-macrophages, or macro-

phages of the second phase of inflammation, cytokine

profile of which (primarily secretion of TGF-β) pro-

vides conditions for incomplete reparative regenera-

tion of the substitution type (scar) [53-55]. Moreover,

under conditions of inflammation the cells-effectors,

neutrophils and macrophages, could themselves de-

stroy frame structures by the secreted proteases (colla-

genases), and in some cases the caused damage could

be even more significant than the damage causing tis-

sue necrosis. For example, it was shown in our stud-

ies that in the photothrombosis-induced kidney dam-

age argyrophilic structures and basement membranes

of the affected renal tubules do not have clearly pro-

nounced changes, and fibrosis development in this

model is associated with the following inflammatory

infiltration of the zone of necrosis [56].

In its turn, one of the conditions of inflammation

development after injury is release of the ligands of

Toll-like receptors and other damage-associated mole-

cules(DAMPs) from the cells subjected to necrotic death

[25, 28, 57-59]. Although, in the case when phagocyto-

sis of apoptotic bodies is delayed for some reason (for

example, when there is at very large number of apop-

totic cells), there is a possibility of their secondary

necrosis accompanied by the development of inflam-

matory response [60], and, consequently, of fibrosis.

Hence, the type of cell death and fate of the dead cell

residues represent another factor determining com-

pleteness of regeneration. And in the case of necrosis

the process usually ends with the development of fi-

brous tissues, rather than regeneration of initial organ

structure.

It must be emphasized that in the case of preserva-

tion of the organ frame structure, organ regeneration

in many cases does need neither exogenous stem cells,

nor even stimulation with growth and differentiation

factors, although these are exactly the key elements

considered essential in the majority of studies devoted

to stimulation of reparative regeneration [16, 18-22].

Itmust be noted that contrary to the conditions asso-

ciated with the state of proliferating parenchymatous

elements, existing in vivo frame structures have not

been discussed in detail in the literature devoted to re-

parative regeneration.

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BIOCHEMISTRY (Moscow) Vol. 89 No. 2 2024

STEM CELLS CAN BUILD ORGAN STRUCTURES

IN THE FREE “MORPHOGENIC SPACE”

Alternative path for building new organ struc-

tures seems also possible, which does not require the

pre-formed organ frame. As is well-known, practical-

ly complete regeneration of organ structures occurs

in newborn animals in the case of non-traumatic kid-

ney injury (for example in experimental ischemia)

[60]. Examination of morphology of neonatal kidney

reveals that new nephrons are still actively forming

from the subcapsular blastema (Fig. 2b). What at-

tracts attention in this case is the cortical area densely

filled with non-differentiated metanephrogenic tissue

containing forming elements of nephrons, as well as

special character of the connective tissues filling the

space between the still sparsely located tubules grow-

ing in the direction from cortex to pelvis. This tissue

consists of mesenchymal-like cells with outgrowths be-

tween which there is almost no collagen but only very

sparse network of reticulin fibers (Fig. 2c). The main

fraction of this tissue comprises a structure-less main

substance, which is clearly visible during staining

with neutral red, thionine, or fast green-FCF(Fig.2c).

It is worth mentioning that very similar tissues have

been observed in the larva of tail-less amphibia, which

apparently provides the possibility of different rear-

rangements during metamorphosis, and also allows

regeneration of lost limbs [61] (it cannot be ruled out

that such differentiation of fibroblasts is indeed a crit-

ical condition providing the possibility of complete

(epimorphic) regeneration of organs and limbs from

blastema in the tailed amphibia). Hence, formation of

new nephrons in kidneys of newborn animals occur

not only in the presence of non-differentiated blaste-

ma, but also in the presence of particular embryonic

connective tissues, which is similar to gelatinous con-

nective tissue within the umbilical cord – Wharton’s

jelly. This tissue featuring abundance of the main sub-

stance and very few rigid fibrous structures, on the

one hand, provides wide-volume space of the organs

(otherwise, in the case of rigid capsule, there would

be mechanical obstacles for formation of new struc-

tures), and on another hand creates three-dimensional

frame, which allows branching and growing in dif-

ferent directions ends of collecting tubules to reach

metanephrogenic blastema without any hurdles, and

increasing length of renal tubules of the new-formed

nephrons [62]. Hence, in this case morphogenesis is re-

alized not in the rigid pre-existing morphogenic frame,

but in a specific free ‘matrix’, which provides possi-

bility of three-dimensional growth of new elements of

parenchyma. Very similar situation is observed invitro

during recreation of organ structures in Matrigel [63].

In the post-fetal period volume of a kidney is filled, in-

stead of matrix, with tubules and with rigid collagen

structures, which makes formation of new nephrons

impossible.

PATHWAYS OF COMPLETE REGENERATION:

PRESERVATION OF FRAME STRUCTURES

AND CREATION OF MORPHOGENIC SPACE

Based on the information presented above several

possibilities facilitating complete regeneration (restitu-

tion) of the damaged organ but not substitution (devel-

opment of fibrous tissue) could be suggested.

First of all, these possibilities include all measures

targeting preservation of the organ frame structure.

1.  Switch the type of cell death from necrotic to

apoptotic (using even paradoxical proactive method

such as addition of apoptosis inducers triggering death

of the cells that under normal conditions would die

by necrosis). Unfortunately, in this respect there are

no particular instructions to certain therapeutic ap-

proaches that would be effective.

2.  Activation of phagocytosis of apoptotic bodies

by macrophages and parenchymatous cells with the

goal of their fastest resorption and prevention of sec-

ondary necrosis and inflammation development. Re-

moval of dead cells occur rather efficiently in kidney

tubules, but is very problematic in liver, where masses

of dead cells could accumulate together with calcium

deposits, which prevents regeneration. Removal of

dead cells is especially important in the case, when it

becomes possible to switch cells from necrotic death to

apoptotic pathway, and the latter one would be mas-

sive. Unfortunately, this approach, as well as the first

one, should be considered at present only as hypothet-

ical. It must be taken into account that fast resorption

of dead tissues could result not in regeneration but at-

rophy of the organ part, if this process is not accompa-

nied with just as fast regeneration or filling of the free

space with matrix.

3.  Inhibition of inflammatory response. For this

purpose, there is a wide range of pharmaceutical

preparations that have been used in clinical practice

for a long time including the cases of alternative pa-

thologies such as coronary heart disease[64]. First of

all, these include new generation of non-steroid an-

ti-inflammatory drugs, as well as inhibitors of proin-

flammatory signaling pathways and cytokines such as

TNFα [64-66]. Although these preparations have not

been investigated with regard to their effects on pres-

ervation of frame structures, there are no directions

for the optimal combination or regime of administra-

tion; at the same time, it is known that some of them

could stimulate fibrosis as a side effect [66].

4.  Inhibition of fibrosis. This pathway has been

considered for a long time, and several approaches

have been suggested including inhibition of fibroblast

ORGAN FRAME ELEMENTS AND REGENERATION 275

BIOCHEMISTRY (Moscow) Vol. 89 No. 2 2024

proliferation and their differentiation to myofibro-

blasts (for example, by affecting signaling pathways

associated with TGF-β), slowing down differentiation

of M2-macrophages, and suppression of collagen syn-

thesis. This seemingly attractive approach is extremely

difficult to implement due to physiological versatility

of molecular mechanisms, which should be suppressed

for this purpose. However, relatively recently first ex-

perimental data have been reported on pharmaco-

logical agents form this group capable of suppressing

development of fibrosis under experimental condi-

tions[67-69].

A different way could be associated with creation

of a morphogenic space in which the exogenously in-

troduced (such as in the case of myocardium) or endog-

enous (in kidney and in liver) stem cells could recreate

organ structures. Such approach could have at least

two strategies.

1)  Creation of artificial cavities and columns with

gelatinous matrix and differentiation factors in the

organ itself. The experimentally tested scaffolds and

‘bioreactors’ with hyaluronic acid could be consid-

ered as close examples (although primitive) of such

approach [52, 67-73], which resulted, for example, in

successful regeneration of limbs in the adult tail-less

amphibia (in which it does not occur naturally, con-

trary to the tailed amphibia)[70].

2)  Strategy associated with changing differenti-

ation of stromal fibroblasts in such a way that they

produce not the fibrous collagen but a ‘matrix’ embry-

onic connective tissues similar to the type of stroma

in the liver of a newborn animal or Wharton’s jelly.

The possibility of using the cells of the latter for the

purposes of regenerative medicine have been consid-

ered, but only from the point of view of production

of pluripotent stem cells [74, 75]. It would be very im-

portant to identify factors inducing differentiation

of such cells and ways of its pharmacological regula-

tion. Existence of the possibility of “Wharton’s” differ-

entiation in the post-fetal tissues is corroborated by

the fact of its appearance under condition of tumor

growth – in the case of myxoma and myxoid stroma

of tumors (Fig. 2d). The latter case is especially inter-

esting, because in this case changes in differentiation

occur in non-tumor cells, and this is often observed

exactly in the differentiated tumors of the adenocar-

cinoma type, which grow via elongation and forma-

tion of new tubules (while the tumors with fibrous

stroma – scirrhous tumors– usually are formed from

the poorly-differentiated tumor cells with extremely

primitive morphogenic processes)[76,77]. These types

of scenarios could serve as models for investigation

of factors inducing ‘myxoid’ stroma in the post-fetal

organism. Induction of differentiation of embryonic

stroma, on the one hand, would allow filling the space

of resorbed dead tissues with the matrix and to pre-

serve this part of the organ from collapse and atro-

phy, and on another hand, to create a foothold for re-

vealing morphogenic potential of local or introduced

stemcells.

CONCLUSIONS

Information presented in this paper allow sug-

gesting that the general reason of failed attempts to

regenerate organ structure after injury by introducing

stem cells or growth factors is destruction of organ

frame elements, which in the majority of vertebrate

animals develop only at the stage of embryonic onto-

genesis. Preservation of these structures is a sufficient

condition for the organ cells capable of proliferation

to rebuilt the organ structure without any external

factors. Another path could be creation of the space

in the organ filled with gelatinous matrix, similarly to

the way it occurs during embryogenesis, by either ar-

tificial introduction or by changing differentiation of

stromal cells and switching their metabolism to syn-

thesis of respective components of intercellular sub-

stance. Creation of organ structures without the pres-

ence of organ frame could be expected in this space,

similarly to the processes occurring in embryogenesis

or reconstruction during amphibia metamorphosis.

However, while the strategies for preservation of or-

gan frame structures seem quite achievable via the al-

ready known methodological approaches, realization

of the second suggestion is at the stage of planning fu-

ture research.

Development of approaches suggested in this re-

view could likely allow to achieve not only complete

regeneration of organ structures from the organism’s

own proliferating and stem cells, but also to succeed

in the cases (heart, nerve tissues), when the necessary

introduction of exogenous stem cells did not yet result

in clinically significant outcomes.

Funding. This work was supported by ongoing in-

stitutional funding. No additional grants to carry out

ordirect this particular research were obtained.

Ethics declarations. This work does not contain

any studies involving human and animal subjects.

The author of this work declares that he has no con-

flicts of interest in financial or any other sphere.

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